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ID PMID Title PublicationDate abstract
26662361 Delayed-Release Dimethyl Fumarate and Pregnancy: Preclinical Studies and Pregnancy Outcome 2015 Dec INTRODUCTION: Delayed-release dimethyl fumarate (DMF; also known as gastro-resistant DMF) is an oral agent for the treatment of relapsing forms of multiple sclerosis (MS). No formal studies of DMF were conducted in pregnant women, although pregnancies have occurred during clinical trials and in the postmarketing setting. METHODS: Preclinical developmental and reproductive toxicology studies were performed with DMF in rats and rabbits. As of March 26, 2014, the DMF clinical development program included a total of 4132 subjects consisting of 2898 patients with MS, 320 psoriasis patients, 101 rheumatoid arthritis patients, and 813 healthy volunteers. Subjects were required to use reliable contraception and immediately discontinue treatment in the event of pregnancy. RESULTS: Animal studies showed no evidence of impaired fertility or teratogenicity with DMF. Overall as of June 30, 2014, 63 pregnancies were reported in clinical trials. Outcomes are known for 39 of 42 subjects receiving DMF and include 26 live births (67%), three spontaneous abortions (8%), and 10 elective terminations (26%); follow-up is ongoing in 2 cases and one patient was lost to follow-up. The incidence of spontaneous abortion in subjects exposed to DMF was consistent with the expected rate of early pregnancy loss in the general population (12-22%). A total of 135 pregnancies were reported in the postmarketing setting (spontaneous and solicited reports). Outcomes are known for 30 cases and include 10 live births, 13 spontaneous abortions, and 5 elective terminations; follow-up is ongoing in 103 cases and 2 patients have been lost to follow-up. CONCLUSION: Although data are limited and all known exposures have occurred in the first trimester, no increased risk of fetal abnormalities or adverse pregnancy outcomes associated with gestational exposure to DMF has been observed. FUNDING: Biogen, Inc.
26497318 A Comparison of Biological Activity of B Lymphocyte Stimulator (BLyS) Antagonist Peptibodi 2016 B lymphocyte stimulator (BLyS) overexpression is associated with autoimmune diseases such as rheumatoid arthritis and lupus. BLyS antagonists are new effective therapeutic strategies that have been studied extensively. BLyS-binding peptides, BC originated from computer-aided drug design (CADD), 814 selected from the phage display library, as well as the 3-copy of BC (3-BC), were fused with human IgG1 Fc to constitute peptide-Fc fusion proteins, referred as peptibodies. BP-Fc, a peptibody possessing the identical sequence as BC-Fc but a His tag, was also constructed. The biological activities of these peptibodies were assessed by Enzyme-Linked Immuno Sorbent Assay (ELISA). Furthermore, the potential interacting orientations of BP and 814 with BLyS were studied. At 100 μg/ml, BC-Fc, BP-Fc, 814-Fc and 3-BC-Fc could distinctly inhibit 64 %, 50 %, 73 % and 56 % of the interaction of B cell maturation antigen (BCMA) with BLyS respectively. BP-Fc demonstrated 15 % higher binding ratio with BLyS than BC-Fc at 100 μg/ml. However, 814-Fc displayed at least 39 % higher BLyS-binding activity than BP-Fc at different concentrations. The binding capacity of 3-BC-Fc was slightly superior to BC-Fc. In addition, 814 and BP shared the identical domain on the surface of BLyS which involves in binding with BCMA, but owned the detached orientations. The discovery of possible locations of the BLyS-targeted peptides lays the foundation for the development of novel antagonists. Both BP-Fc and 3-BC-Fc fusion proteins could bind to BLyS in a dose-dependent manner and inhibit BLyS biological activity significantly, which might act as candidate agents for autoimmune disease therapy.
26452851 A novel salting-out assisted extraction coupled with HPLC- fluorescence detection for trac 2015 Nov 1 Recently, new physiological roles of vitamin K homologues have been established in the treatment of rheumatoid arthritis, osteoporosis, hepatocellular carcinoma and leukemia. However, relatively high plasma protein binding, low plasma concentrations and occurrences of interfering lipids make accurate determination of vitamin K homologues a challenging task. Therefore, a sensitive and reliable salting-out assisted liquid/liquid extraction (SALLE) method coupled with HPLC-Fluorescence detection was designed for efficient extraction and quantification of trace levels of vitamin K homologues in human plasma. The investigated vitamin K homologues were phylloquinone (PK, vitamin K1), menaquinone-4 (MK-4) and menaquinone-7 (MK-7). The method employed a new efficient fluorescence derivatization reaction using ethanolic solution of stannous chloride in acidic solution to generate highly fluorescent naphthohydroquinone derivatives. Correlation coefficients were more than 0.998 in the concentration ranges of 0.3-100 ng mL(-1) with detection limits of 0.1-0.17 ng mL(-1) in human plasma. The developed HPLC-FL system was successfully applied for sensitive determination of vitamin K homologues in plasma of healthy volunteers. The developed method may provide a valuable tool in the pharmacoinformatic studies concerning the roles of vitamin K homologues.
26440665 Neutralizing Antibody Response after Intramuscular Purified Vero Cell Rabies Vaccination ( 2015 OBJECTIVE: Post exposure prophylaxis using one of the WHO-approved vaccines is the method of choice for preventing rabies. Abnormal immune function in patients with some specific medical conditions, such as pregnancy, chronic hepatitis B virus infection, different types of cancers like lymphoma, diabetes I and II, corticosteroid consumption by patients with rheumatoid arthritis and lupus erythematosus, could impair the immunologic response to various vaccines. The immune response to rabies vaccination has never been examined in patients with any of these described medical conditions. This study purposed to evaluate the neutralyzing antibody response after vaccination with purified Vero cell rabies vaccine (PVRV) according to the WHO-recommended Post-Exposure Prophylaxis (PEP) "ESSEN" regimen. METHODS: Thirty healthy volunteers and 50 volunteers with different medical conditions who were exposed to a suspected rabid animal in the 2nd or 3rd category of exposure received 5 doses of PVRV under the ESSEN protocol. Three blood samples were collected on days 0 (before the first dose), 14, and 35. The anti-rabies antibody titer was measured using the Rapid Fluorescent Foci Inhibition Test (RFFIT) and an ELISA Bio-Rad, Platelia, Rabies II kit. RESULTS: All subjects reached NAb titers above 0.5 IU/ml by day 14 after vaccination. On day 35 (1 week after receiving the last rabies vaccine), anti-rabies antibodies were in the protective level (>0.5 IU/ml) in both groups. There was no statistically significant difference in anti-rabies antibody response due to the type of exposure (category 2 or 3), and successful seroconversion was confirmed in both groups. CONCLUSION: In conclusion, the ESSEN protocol using the PVRV vaccine is sufficient for rabies prophylaxis in patients with specific medical conditions.
26365281 Review article: pharmacological aspects of anti-TNF biosimilars in inflammatory bowel dise 2015 Nov BACKGROUND: Anti-tumour necrosis factor (anti-TNF) monoclonal antibodies have shown efficacy in inflammatory bowel diseases (IBD). As these therapies lose patent protection, biosimilar versions of the originator products are being developed, such as the infliximab biosimilar CT-P13; however, some uncertainty exists regarding their pharmacology in IBD. AIM: To review the literature on anti-TNF biosimilars focusing on pharmacokinetics, pharmacodynamic properties and comparative effectiveness, related to their use in IBD. METHODS: A PubMed literature search was performed using the following terms individually or in combination: 'biosimilars,' 'CT-P13,' 'Crohn's disease,' 'inflammatory bowel disease,' 'ulcerative colitis,' 'anti-TNFα therapy,' 'infliximab,' 'adalimumab,' 'pharmacokinetics,' 'immunogenicity.' RESULTS: Bioequivalence of CT-P13 and infliximab was shown in ankylosing spondylitis (AS) and therapeutic equivalence in rheumatoid arthritis (RA). Preliminary results of CT-P13 in IBD come from small post-marketing registries and case series with a relatively short-term follow-up period and suggest comparable efficacy and safety to infliximab. Inter- and intra-individual differences in exposure and response are well known for the original molecules but dosing regimens and concomitant medications are different for RA compared to IBD, limiting the ability to translate some of the pharmacology data in RA to IBD. Uncertainty exists about cross-reactivity of anti-drug antibodies and whether similar exposure-response relationships will be observed for biosimilars and efficacy thresholds for therapeutic drug monitoring can be used interchangeably. CONCLUSIONS: It is likely that biosimilars will be widely used for the treatment of IBD due to their cost savings and comparable efficacy. Nevertheless, robust post-marketing studies and pharmacovigilance are warranted in the coming years.
26338723 Metal complexes of pyridine-fused macrocyclic polyamines targeting the chemokine receptor 2015 Nov 14 The chemokine receptor CXCR4 acts as a key cell surface receptor in HIV infections, multiple forms of cancer, and various other pathologies, such as rheumatoid arthritis and asthma. Macrocyclic polyamines and their metal complexes are known to exert anti-HIV activity, many acting as HIV entry inhibitors by specifically binding to CXCR4. Three series of pyridopentaazacylopentadecanes, in which the pyridine ring is fused to zero, one, or two saturated six-membered rings, were synthesized by manganese(ii)-templated Schiff-base cyclization of triethylenetetramine with various dicarbonyl compounds. By evaluating these macrocyclic polyamines and their complexes with Mn(2+), Cu(2+), Fe(3+), and Zn(2+), we have discovered novel CXCR4-binding compounds. The MnCl2 complex of a new pentaazacyclopentadecane with one fused carbocyclic ring (11) was found to have the greatest potency as an antagonist of the chemokine receptor CXCR4 (IC50: 0.014 μM), as evidenced by inhibiting binding of CXCL12 to PBMCs (peripheral blood mononuclear cells). Consequently, this compound inhibits replication of the CXCR4-using (X4) HIV-1 strain NL4-3 in the TZM-bl cell line with an IC50 value of 0.52 μM and low cytotoxicity (CC50: >100 μM). In addition, 18 other compounds were evaluated for their interaction with CXCR4 via their ability to interfere with ligand chemokine binding and HIV entry and infection. Of these, the metal complexes of the two more hydrophobic series with one or two fused carbocyclic rings exhibited the greatest potency. The Zn(2+) complex 21 was among the most potent, showing that redox activity of the metal center is not associated with CXCR4 antagonist activity.
26059596 Discovery of 3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one derivatives as novel 2015 Aug 1 Because Janus kinases (JAKs) play a crucial role in cytokine-mediated signal transduction, JAKs are an attractive target for the treatment of organ transplant rejection and autoimmune diseases such as rheumatoid arthritis (RA). To identify JAK inhibitors, we focused on the 1H-pyrrolo[2,3-b]pyridine derivative 3, which exhibited moderate JAK3 and JAK1 inhibitory activities. Optimization of 3 identified the tricyclic imidazo-pyrrolopyridinone derivative 19, which exhibited potent JAK3 and JAK1 inhibitory activities (IC50=1.1 nM, 1.5 nM, respectively) with favorable metabolic stability.
25992551 Tumor grafting induces changes of gut microbiota in athymic nude mice in the presence and 2015 Recent findings have revealed that gut microbiota plays a substantial role in modulating diseases such as autism, rheumatoid arthritis, allergies, and cancer that occur at sites distant to the gut. Athymic nude mice have been employed for tumorigenic research for decades; however, the relationships between the gut microbiome and host's response in drug treatment to the grafted tumors have not been explored. In this study, we analyzed the fecal microbiome of nonxenograft and xenograft nude mice treated with phytosaponins from a popular medicinal plant, Gynostemma pentaphyllum (Gp). Analysis of enterobacterial repetitive intergenic consensus (ERIC)-PCR data showed that the microbiota profile of xenograft mice departed from that of the nonxenograft mice. After ten days of treatment with Gp saponins (GpS), the microbiota of the treated mice was closer to the microbiota at Day 0 before the implantation of the tumor. Data obtained from 16S pyrosequencing of fecal samples reiterates the differences in microbiome between the nonxenograft and xenograft mice. GpS markedly increased the relative abundance of Clostridium cocleatum and Bacteroides acidifaciens, for which the beneficial effects on the host have been well documented. This study, for the first time, characterizes the properties of gut microbiome in nude mice responding to tumor implant and drug treatment. We also demonstrate that dietary saponins such as GpS can potentially regulate the gut microbial ecosystem by increasing the number of symbionts. Interestingly, this regulation of the gut ecosystem might, at least in part, be responsible for or contribute to the anticancer effect of GpS.
25725106 Collagen induces maturation of human monocyte-derived dendritic cells by signaling through 2015 Apr 1 Osteoclast-associated receptor (OSCAR) is widely expressed on human myeloid cells. Collagen types (Col)I, II, and III have been described as OSCAR ligands, and ColII peptides can induce costimulatory signaling in receptor activator for NF-κB-dependent osteoclastogenesis. In this study, we isolated collagen as an OSCAR-interacting protein from the membranes of murine osteoblasts. We have investigated a functional outcome of the OSCAR-collagen interaction in human monocyte-derived dendritic cells (DCs). OSCAR engagement by ColI/II-induced activation/maturation of DCs is characterized by upregulation of cell surface markers and secretion of cytokines. These collagen-matured DCs (Col-DCs) were efficient drivers of allogeneic and autologous naive T cell proliferation. The T cells expanded by Col-DCs secreted cytokines with no clear T cell polarization pattern. Global RNA profiling revealed that multiple proinflammatory mediators, including cytokines and cytokine receptors, components of the stable immune synapse (namely CD40, CD86, CD80, and ICAM-1), as well as components of TNF and TLR signaling, are transcriptional targets of OSCAR in DCs. Our findings indicate the existence of a novel pathway by which extracellular matrix proteins locally drive maturation of DCs during inflammatory conditions, for example, within synovial tissue of rheumatoid arthritis patients, where collagens become exposed during tissue remodeling and are thus accessible for interaction with infiltrating precursors of DCs.
25524576 Leishmanial sphingolipid induces apoptosis in Sarcoma 180 cancer cells through regulation 2015 Apr Sphingolipids are membrane and intracellular lipids that typically modulate cellular processes to cause cell death. Exogenous administration of sphingolipids may cause restriction of tumour growth and several alternative strategies are being used to control the cell growth. The microbes, their cellular component(s) or metabolites like DHA, EPA and also FTY720 have been employed as new therapeutic entities to regulate the disease condition. The therapeutic efficacy of lipids from Leishmania donovani in rheumatoid arthritis and also in sepsis condition associated with inflammatory diseases is well established. In this study, we explored the apoptotic effect of LSPL-1 (leishmanial sphingolipid-1) in Sarcoma 180 cells towards the regulation of tumour growth. The study using a panel of cancer cell lines revealed that LSPL-1 induces cell death in Sarcoma 180. The apoptotic changes were assessed by annexin exposure and DNA content analysis using flow cytometry. LSPL-1 appears to activate several pro- and anti-apoptotic molecules through reactive oxygen species (ROS) generation and also caspase activation, as determined by Western blot and ELISA analyses. Simultaneously, it may improve the survival rate of mice bearing tumour induced by Sarcoma 180 cells, with pathological changes. LSPL-1 may also suppress the cancer-associated inflammatory responses with the expression of matrix metalloproteinase having inhibitory role. It may regulate several angiogenic factors including VEGF, Ang-2 and CD34 in angiogenic events generated in Sarcoma 180 cell-induced tumour. These studies underline the significance of anti-neoplastic potential of LSPL-1 through apoptosis induction and abrogation of angiogenic responses in Sarcoma 180 cell-associated tumour.
25391768 Soluble overexpression and purification of bioactive human CCL2 in E. coli by maltose-bind 2015 Mar Human chemokine (C-C motif) ligand 2 (hCCL2) is a small cytokine in the CC chemokine family that attracts monocytes, memory T lymphocytes, and natural killer cells to the site of tissue injury- or infection-induced inflammation. hCCL2 has been implicated in the pathogeneses of diseases characterized by monocytic infiltrates, including psoriasis, rheumatoid arthritis, atherosclerosis, multiple sclerosis, and insulin-resistant diabetes. The prokaryotic overexpression of hCCL2 has been investigated previously in an attempt to develop biomedical applications for this factor, but this has been hampered by protein misfolding and aggregation into inclusion bodies. In our present study, we screened 7 protein tags-Trx, GST, MBP, NusA, His8, PDI, and PDIb'a'-for their ability to allow the soluble overexpression of hCCL2. Three tags-MBP, His8, and PDI-solubilized more than half of the expressed hCCL2 fusion proteins. Lowering the expression temperature to 18 °C significantly further improved the solubility of all fusion proteins. MBP was chosen for further study based on its solubility, expression level, ease of purification, and tag size. MBP-CCL2 was purified using conventional chromatography and cleaved using TEV or Factor Xa proteases. Biological activity was assessed using luciferase and cell migration assays. Factor Xa-cleaved hCCL2 was found to be active and TEV-cleaved hCCL2 showed relatively less activity. This is probably because the additional glycine residues present at the N-terminus of hCCL2 following TEV digestion interfere with the binding of hCCL2 to its receptor.
25294523 Hospital admissions greater than 30 days following bariatric surgery: patient and procedur 2015 Jun INTRODUCTION: Assessment of hospital admission in the 30-day period following bariatric surgery likely underestimates true hospital utilization. The purpose of this study is to assess hospital admissions for 2 years following bariatric surgery to identify potential differences by patient and procedure. METHODS: New York State Planning and Research Cooperative System (SPARCS) longitudinal administrative data were used to identify 22,139 adult patients who underwent a primary bariatric surgery from 2006 to 2008. Bariatric operations included laparoscopic gastric banding (LGB), laparoscopic Roux-en-y gastric bypass (RYGB), and laparoscopic sleeve gastrectomy (LSG). Patients were followed for 2 years after surgery to identify all-cause hospital admissions. Statistical correlation between postoperative hospital admission and patient demographics, comorbid conditions, and bariatric procedure was performed. RESULTS: Of the 22,139 patients, 5,718 (26 %) patients were admitted within 2 years of surgery for a total of 9,502 admissions. Thirty-day admission rate was 5 %. The number of admissions per patient ranged from 1 to 22. Assessing the number of admissions per patient demonstrated that 3,741 (17 %) patients had one, 1,575 (7 %) had 2-3, and 402 (2 %) patients had greater than 4 admissions. LSG had both the highest admission rate and percentage of patients with >4 admissions, followed by RYGB and then LGB (p < 0.001). Risk factors for admission included black race, female gender, age > 50, Medicaid/Medicare as payer, congestive heart failure, pulmonary disease, diabetes, rheumatoid arthritis, history of substance abuse, and psychoses/depression. CONCLUSION: One out of four bariatric patients will be admitted to the hospital within 2 years of surgery. While most patients are admitted only once, a subset of patients requiring numerous hospital admissions was identified. LSG is associated with both the highest rate as well as highest frequency of hospital admissions. Several patient factors were also identified that significantly increased admission risk. Consideration and attention to these factors are necessary for operative planning, preoperative patient education, and postoperative monitoring.
25045124 Leptin induces ADAMTS-4, ADAMTS-5, and ADAMTS-9 genes expression by mitogen-activated prot 2015 Jan Elucidation of the causes of inflammation has vital importance in the development of new approaches for the treatment of arthritic diseases. The degradation of aggrecan by upregulated disintegrin and metalloproteinase with trombospondin motifs (ADAMTSs) is the key event in the development of both rheumatoid arthritis (RA) and osteoarthritis (OA). Increased levels of leptin in both RA and OA have been demonstrated, thus linking leptin to arthritic diseases, but the mechanism has not been clarified. This study investigated the putative role of signaling pathways (p38, JNK, MEK1, NF-ĸB, and PI3) involved in leptin-induced cartilage destruction. Normal human articular chondrocytes were cultured with recombinant human leptin at 100, 250, 500, and 1000 ng/mL doses for 6, 12, 24, and 48 h, after which ADAMTS-4, -5, and -9 genes expression were determined by real time-polymerase chain reaction (RT-PCR) and Western Blot methods. The signaling pathways involved in leptin-induced ADAMTSs upregulation were also investigated by using inhibitors of signaling pathways. It was demonstrated that ADAMTSs expression level was peaked at 1000 ng/mL doses for 48 hours, and MAPKs (p38, JNK, and MEK) and NF-ĸB signaling pathways involving in leptin triggered ADAMTSs upregulation. Obesity as a risk for RA and OA may contribute to the inflammation of both RA and OA diseases by secreting adipokines like leptin. We hypothesize that leptin is involved in the development of RA and OA accompanied with obesity by increasing ADAMTS-4, -5, and -9 genes expression via MAPKs and NF-ĸB signaling pathways.
27022522 WRIST ARTHRODESIS WITH MINIMAL FIXATION PRESERVING THE CARPOMETACARPAL JOINTS. 2010 Jan OBJECTIVE: Wrist arthrodesis is a surgical procedure that should always be considered in cases of pathological conditions in which anatomical and functional structures are altered. In general, the results are very satisfactory, particularly for pain relief, and in the majority of cases, there is considerable functional improvement. Various techniques have been described, with different methods of internal fixation, most of which include the carpometacarpal joints in the fusion. The objective of this study was to evaluate the results from wrist arthrodesis using a technique that is simpler, more biological, less expensive, and does not involve the carpometacarpal joints. METHODS: Fifteen patients with wrist arthrodesis were evaluated (six with sequelae from trauma, four with rheumatoid arthritis, three with Kienbock grade IV, one with Preiser and one with panarthrosis). The technique consisted of using an iliac bone plate and internal fixation with Kirschner wires, avoiding the carpometacarpal joints. RESULTS: The evaluation was based on consolidation time (93% in seven weeks); movements of the fingers and pronosupination; pinch and grasp strength; functional evaluation through the DASH, pain and patient satisfaction questionnaires. In general, the results were similar to those of other, more aggressive techniques, and the non-inclusion of the carpometacarpal joints did not affect the final result. CONCLUSION: Wrist arthrodesis with fixation using Kirschner wires and an iliac bone plate, preserving the carpometacarpal joints, gives good or excellent results that are not inferior to those of other techniques that have been described. However, it presents major advantages over other methods: it is less aggressive and cheaper, and does not have the inconvenience and complications associated with the use of plates and screws.
28987361 Comparative effect of horse gram and black gram on inflammatory mediators and antioxidant 2017 Oct A balanced diet is important for the overall wellbeing of an individual. Pulses are an important part of a nutritive diet. Pulses have been consumed for at least 10,000 years and are among the most extensively used foods in the world. They are a rich source of protein and fiber, as well as a significant source of vitamins and minerals, such as iron, zinc, and magnesium. The purpose of this study was to compare the effect of two pulses, horse gram and black gram, on inflammatory mediators and the antioxidant enzymes. Two sets of experiments were conducted in rats which were fed with boiled and unboiled horse gram and black gram, at a dose of 100 mg/100 g body weight, for 21 days and 60 days. The results showed that horse gram supplementation for 21 days and 60 days significantly increased the activities of antioxidant enzymes such as superoxide dismutase, catalase, glutathione peroxidase and showed no significant changes in the activities of the inflammatory mediators such as cyclooxygenase, lipoxygenase, myeloperoxidase, nitric oxide synthase, monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-alpha (TNF-α), interleukin-1-beta (IL-1β), etc. However, the black gram (with skin and without skin) supplementation significantly increased activities of the inflammatory mediators and showed a significant decrease in the antioxidant enzymes in both the 21-day and 60-day experiments. Thus, these preliminary results demonstrate the anti-inflammatory and antioxidant potential of horse gram and the proinflammatory effects of black gram in rats. This is in accordance with the dietary regime advised by Ayurveda practitioners, where horse gram is to be included and black gram is to be excluded from the diet for conditions such as rheumatoid arthritis. Further studies are to be conducted to validate the same.
28378008 Surgical site infection and transfusion rates are higher in underweight total knee arthrop 2017 Mar BACKGROUND: Underweight (UW) patients undergoing total hip arthroplasty have exhibited higher complication rates, including infection and transfusion. No study to our knowledge has evaluated UW total knee arthroplasty (TKA) patients. We, therefore, conducted a study to investigate if these patients are at increased risk for complications, including infection and transfusion. METHODS: A case-control study was conducted using a prospectively collected institutional database. Twenty-seven TKA patients were identified as UW (body mass index [BMI] < 18.5 kg/m(2)) from 2000-2012 and were matched for age, gender, date of surgery, age-adjusted Charlson comorbidity index, rheumatoid arthritis, and diabetes. These patients were compared to 81 normal weight patients (BMI 18.5-24 kg/m(2)). Demographic variables were compared, along with wound complications, surgical site infection (SSI), blistering, deep vein thrombosis, pulmonary embolism, transfusion, revision, flexion contracture, hematoma formation, and patellar clunk. RESULTS: The average BMI was 17.1 kg/m(2) (range 12.8-18.4) for UW and 23.0 kg/m(2) (range 19.0-25.0) for normal weight patients (P < .001). UW TKA patients were more likely to develop SSIs (3/27, 11.1% vs 0/81, 0.0%, P = .01) and were more likely to require transfusions (odds ratio = 3.4, confidence interval 1.3-9.1; P = .02). CONCLUSIONS: Our study demonstrates that UW TKA patients have a higher likelihood of developing SSI and requiring blood transfusions. The specific reasons are unclear, but we conjecture that it may be related to decreased wound healing capabilities and low preoperative hemoglobin. Investigation of local tissue coverage and hematologic status may be beneficial in this patient population to prevent SSI. Based on the results of this study, a prospective evaluation of these factors should be undertaken.
27671821 Celastrol and Its Role in Controlling Chronic Diseases. 2016 Celastrol, a triterpenoid derived from traditional Chinese medicinal plants, has anti-inflammatory, antioxidant, and anticancer activities. Celastrol has shown preventive/therapeutic effects in experimental models of several chronic diseases. These include, chronic inflammatory and autoimmune diseases (e.g., rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, inflammatory bowel disease, and psoriasis), neurodegenerative disorders (e.g., Alzheimer's disease, Parkinson's disease, and Amyotrophic lateral sclerosis), atherosclerosis, obesity, Type 2 diabetes, and cancer. Celastrol modulates intricate cellular pathways and networks associated with disease pathology, and it interrupts or redirects the aberrant cellular and molecular events so as to limit disease progression and facilitate recovery, where feasible. The major cell signaling pathways modulated by celastrol include the NF-kB pathway, MAPK pathway, JAK/STAT pathway, PI3K/Akt/mTOR pathway, and antioxidant defense mechanisms. Furthermore, celastrol modulates cell proliferation, apoptosis, proteasome activity, heat-shock protein response, innate and adaptive immune responses, angiogenesis, and bone remodeling. Current understanding of the mechanisms of action of celastrol and information about its disease-modulating activities in experimental models have set the stage for testing celastrol in clinical studies as a therapeutic agent for several chronic human diseases.
27614763 Novel Piperazino-Enaminones Suppress Pro-Inflammatory Cytokines and Inhibit Chemokine Rece 2016 Dec Pro-inflammatory mediators including TNF-alpha, IL-6, and nitric oxide are important for the regulation of the immune response when an infection is present, but when overproduced, it can be responsible for the development of tissue and organ injury seen in sepsis, as well as severe asthma, and autoimmune diseases such as Crohn's disease and rheumatoid arthritis. Data from our lab to characterize the novel compound enaminone E121 have suggested that macrophages stimulated with lipopolysaccharide (LPS) release significantly decreased levels of TNF-alpha and IL-6 as measured by enzyme-linked immunosorbent assay as compared to the DMSO control group. Additionally, functional experiments in a mouse model of asthma have shown that E121 is efficacious in decreasing airway hyperresponsiveness. A new set of compounds synthesized in our lab (JODI) have an N-aryl piperazino motif incorporated on the aromatic side of the enaminone pharmacophore. It was hypothesized that this would enhance their immunosuppressive activity as anti-inflammatory agents by also acting as a chemokine receptor antagonist. Our studies suggest that JODI appears to suppress TNF-alpha and IL-6 in a dose-dependent manner. The JODI compounds were also more effective in reducing TNF-alpha after LPS stimulation when compared to dexamethasone. Lastly, studies using MCP-1 suggest that the JODI compounds, and not E121, are able to block CCR2 signaling as evidenced by decreased total ERK1/2. These studies indicate that E121 and its corresponding piperazino analogs could act as strong anti-inflammatory agents in asthma or other autoimmunities where efficacious therapeutic options are needed.
27559841 Effects of Miconazole Oral Gel on Blood Concentrations of Tacrolimus and Cyclosporine: A R 2016 Dec BACKGROUND: Although azole antifungal agents have been shown to affect the pharmacokinetics of calcineurin inhibitors such as tacrolimus (TAC) and cyclosporine (CyA) by inhibiting drug metabolism, there are few clinical reports on drug interactions between miconazole (MCZ) oral gel and calcineurin inhibitors. In this study, the effects of MCZ oral gel on the blood concentrations of TAC and CyA were investigated. METHODS: In this retrospective study, 18 patients concomitantly administered MCZ oral gel and TAC (9 for dermatomyositis, 3 for myasthenia gravis, 2 for systemic lupus erythematosus, 2 for rheumatoid arthritis, 1 for polymyositis, 1 for prevention of graft-versus-host disease after bone marrow transplantation), and 15 patients concomitantly administered MCZ oral gel and CyA (11 for interstitial pneumonia, 2 for pemphigus, 1 for eosinophilic granulomatosis with polyangiitis, 1 for systemic lupus erythematosus) were evaluated. The dose-adjusted blood concentrations of TAC or CyA were compared before and after the initiation of MCZ oral gel. RESULTS: The trough blood concentration/dose (C/D) ratios of TAC and CyA increased significantly with the administration of MCZ oral gel. The median C/D ratios of TAC and CyA increased by 108% (range: -44% to 216%) and 44% (range: -34% to 195%), respectively. CONCLUSIONS: These results suggest that MCZ oral gel affects the pharmacokinetics of TAC and CyA. Detailed monitoring of the blood concentrations of these drugs, followed by dose adjustments, is needed for each patient because of the difficulties associated with accurately predicting the degree of the effects of MCZ oral gel.
27512223 Relation between the development of osteoporosis and osteonecrosis following glucocorticoi 2016 Jul BACKGROUND: There has been a recent increase in the number of patients suffering from bone and joint diseases, as a consequence of corticosteroids administration. There are more patients treated with low dose of GCs under long-term conditions in clinical, such as effect of GCs on Rheumatoid arthritis, Crohn's disease and Asthma patients. Hence, it was difficult for doctor to determine which problem occur first - OP or ON; however, there was no clinical report previously in the literature, and there was no effective animal model of OP and ON about low dose GCs. This study was conducted to develop rabbit models of glucocorticoid (GC)-induced femoral head ON and OP and to investigate the temporal relationship between the occurrence of the two events following administration of glucocorticoids. MATERIALS AND METHODS: Fifty six, 6 months old female rabbits were randomly divided into the GC group and control group (C). Rabbits received gluteal injections of methylprednisolone sodium succinate once a day for 4 weeks, while normal saline solution in the control group. Rabbits were sacrificed at 0, 2, 4, and 8 weeks. Hip magnetic resonance imaging was performed before the rabbits were sacrificed. Serum calcium (Ca), phosphorus (P), total cholesterol, and triglyceride levels were also measured. The bone mineral density (BMD) of femoral head and the femoral shaft were measured by dual-energy X-ray absorptiometry. The trabecular parameters of the femur and the 4(th) lumbar vertebrae (L4) were measured with a micro-computed tomography (μ-CT). Also, the femoral head was stained with hematoxylin-eosin staining. RESULTS: At 4 weeks in the GC group, the BMD of the femur reduced 33% and 22% in the femoral head and shaft; there was irregular intermediate to high T2-weighted images signals; μ-CT showed microfractures and cystic changes in the femoral head and L4 at 4 weeks. At 8 weeks in the GC group, the classical "line-like sign" indicating ON of the femoral head was observed in 64.3% of the rabbits. CONCLUSION: A rabbit model of GC-induced OP and ON was developed by repetitive injection with small doses of GCs in the gluteal region. OP was observed at 4 weeks while ON developed at 8 weeks and followed a clear temporal pattern.