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ID PMID Title PublicationDate abstract
27185240 The effects in vitro of TNF-α and its antagonist 'etanercept' on ejaculated human sperm. 2017 Jun Tumour necrosis factor (TNF)-α is primarily involved in the regulation of cell proliferation and apoptosis; in addition it possesses pro-inflammatory properties. Anti-TNF-α strategies involve either administration of anti-TNF-α antibody or soluble TNF receptor to mop up circulating TNF-α. Etanercept, a recombinant human TNF-α receptor, was found to be effective in the treatment of rheumatoid arthritis. The impact of TNF-α inhibitors on human fertility is of notable interest. This in vitro study investigated the effect of different concentrations of TNF-α and etanercept used alone or in combination on sperm viability, motility, mitochondrial function, percentage of apoptosis and chromatin integrity in swim-up selected human spermatozoa. A negative effect of TNF-α (300 and 500ng mL(-1)) and etanercept (from 800µg mL(-1) to 2000µg mL(-1)) individually on sperm viability, motility, mitochondrial function, percentage of apoptotic spermatozoa and sperm DNA integrity was demonstrated. However, at concentrations of 100 and 200µg mL(-1), etanercept can block, in a significant way, the toxic effects of TNF-α (500ng mL(-1)) on studied sperm characteristics. Our results confirm that TNF-α has a detrimental effect on sperm function and suggest, for the first time, that etanercept may counteract the in vitro toxic action of TNF-α. This data appears to be quite promising, although further studies, both in vivo and in vitro, are needed to understand the exact mechanism of action of TNF-α and TNF-α antagonists on sperm function.
29086909 Acid-sensing ion channel 1a mediates acid-induced inhibition of matrix metabolism of rat a 2018 Jun The acid-sensing ion channel 1a (ASIC1a), which is activated by extracellular acid, contributes to the pathogenesis of rheumatoid arthritis. However, it remains unclear whether ASIC1a mediates acid-induced matrix metabolism in rat articular chondrocytes via activation of the MAPK signaling pathway. In the current study, we found that extracellular acidification (pH 6.0) inhibited proliferation and induced apoptosis of articular chondrocytes in a dose-dependent manner, while the expression of phosphorylated ERK1/2 and P38 MAPK increased, but, this effect was blocked by the Ca(2+) chelator BAPTA-AM and the ASIC1a-specific blocker PcTx-1. In addition, extracellular acidification increased the expression of c-fos, GAG, HYP, and TIM1/2. These effects were inhibited by the Ca(2+) chelator BAPTA-AM, ERK1/2 inhibitor PD98059, and ASIC1a-specific blocker PcTx-1, but not the P38 MAPK inhibitor SB203580. Finally, extracellular acidification increased the expression of c-jun and MMP-2/9, and these effects were blocked by the Ca(2+) chelator BAPTA-AM, P38 MAPK inhibitor SB203580, and ASIC1a-specific blocker PcTx-1, but not the ERK1/2 inhibitor PD98059. In conclusion, ASIC1a inhibits the expression of MMP-2/9, GAG, HYP, and TIMP-1/2 by the Ca(2+)-dependent P38 MAPK/c-jun and ERK/c-fos signaling pathways.
29086866 Synthesis, crystallographic characterization, molecular docking and biological activity of 2017 Oct 16 The main objective of this work was to synthesize novel compounds with a benzo[de][1,2,4]triazolo[5,1-a]isoquinoline scaffold by employing (dioxo-benzo[de]isoquinolin-2-yl) thiourea as a building block. Molecular docking was conducted in the COX-2 active site to predict the plausible binding mode and rationalize the structure-activity relationship of the synthesized compounds. The structures of the synthesized compounds were confirmed by HREI-MS, and NMR spectra along with X-ray diffraction were collected for products 1 and 5. Thereafter, anti-inflammatory effect of molecules 1-20 was evaluated in vivo using carrageenan-induced paw edema method, revealing significant inhibition potency in albino rats with an activity comparable to that of the standard drugs indomethacin. Compounds 8, 9, 15 and 16 showed the highest anti-inflammatory activity. However, thermal sensitivity-hot plat test, a radiological examination and motor coordination assessment were performed to test the activity against rheumatoid arthritis. The obtained results indicate promising anti-arthritic activity for compounds 9 and 15 as significant reduction of the serum level of interleukin-1β [IL-1β], cyclooxygenase-2 [COX-2] and prostaglandin E2 [PGE2] was observed in CFA rats.
29074274 Cellular and functional actions of tofacitinib related to the pathophysiology of hibernoma 2017 Dec Tofacitinib is an oral JAK inhibitor for the treatment of rheumatoid arthritis. In the 2-year carcinogenicity study with tofacitinib, increased incidence of hibernoma (a neoplasm of brown adipose tissue [BAT]) was noted in female rats at ≥30 mg/kg/day (≥41x human exposure multiples). Thus, signaling pathways within BAT were investigated by measuring BAT: weight, cell proliferation biomarkers, content of basal and prolactin-induced phosphorylated Signal Transducer and Activator of Transcription (STAT), and uncoupling protein 1 (UCP-1). The relationship between cardiovascular hemodynamics and plasma norepinephrine (NE) levels was also investigated. Tofacitinib administered to female rats at doses of 10, 30, or 75 mg/kg/day for 14 days increased BAT weight at 75 mg/kg/day and cell proliferation at ≥30 mg/kg/day. JAK inhibition, observed as lower pSTAT3 and pSTAT5 in BAT, was noted at ≥10 mg/kg/day, while lower activity of BAT was observed as lower UCP-1 protein at ≥30 mg/kg/day. In cultured brown adipocytes, prolactin-induced increase in pSTAT5 and pSTAT3 were inhibited by tofacitinib in a concentration-dependent manner. Tofacitinib lowered blood pressure, increased heart rate, and resulted in dose-dependent increases in circulating NE. Thus, JAK/STAT inhibition in BAT and sympathetic stimulation are two factors which might contribute to the genesis of hibernomas by tofacitinib in rats.
29039456 Construction of a Bcl-2-shRNA expression vector and its effect on the mitochondrial apopto 2017 Dec Apoptosis is considered to serve an important role in the pathogenesis of rheumatoid arthritis. The aim of the present study was to construct Bcl-2-short hairpin (sh)RNA expression vectors and transfect them into human synovial sarcoma SW982 cells, in order to screen for an effective interference sequence and analyze the effects of this interference on the expression levels of Bcl-2 and other molecules associated with the mitochondrial apoptosis pathway. Three different shRNAs (Bcl-2-sh1, 2 and 3) were designed according to the human Bcl-2 mRNA target sequence and were transformed into competent DH5α Escherichia coli cells following the construction of an expression vector, which was then transfected into SW982 cells. SW982 cells were grouped into a control group (transfected with a negative control shRNA), and Bcl-2-sh1, Bcl-2-sh2 and Bcl-2-sh3 groups (transfected with Bcl-2-sh1, 2 and 3, respectively). The expression levels of Bcl-2 mRNA were detected using reverse transcription-quantitative PCR (RT-qPCR). Bcl-2-sh1 was identified as the most effective shRNA sequence for interference, and was used for subsequent experiments. The mRNA and protein expression levels of Bcl-2, Bax, CytC and Caspase-3 were detected in SW982 cells by RT-qPCR and western blotting at various time-points (48 and 72 h) following transfection with Bcl-2-sh1, in order to observe the effectiveness of this interference. Compared with the control group, the expression levels of Bcl-2 were decreased, while those of Bax, CytC and Caspase-3 were increased in Bcl-2-sh1-transfected cells (P<0.01). The interference effect was greater at 48 h than at 72 h. In summary, an effective shRNA sequence (Bcl-2-sh1) targeting the Bcl-2 gene was identified from three candidates, and was demonstrated to significantly interfere with the expression of Bcl-2, Bax, CytC and Caspase-3 when transfected into SW982 cells. The interference effect of Bcl-2-sh1 was more pronounced at 48 h than at 72 h post-transfection.
28459415 FRAX-based Estimates of 10-year Probability of Hip and Major Osteoporotic Fracture Among A 2017 Mar BACKGROUND: The FRAX algorithm estimates the 10-year probability of hip and major osteoporotic (clinical spine, forearm, hip, or humerus) fracture for adults aged 40 and over. An expert panel developed criteria to define elevated FRAX probabilities for U.S. adults aged 50 and over. This report uses FRAX estimates from the National Health and Nutrition Examination Survey 2013-2014 to describe the hip and major osteoporotic fracture probability distribution (for adults aged 40 and over) and prevalence of elevated probabilities (for adults aged 50 and over) in the United States. METHODS: FRAX U.S. version 3.05 was used to calculate fracture probability from risk factors that were measured (i.e., femur neck bone mineral density, height, and weight) or self-reported (i.e., fracture history, glucocorticoid use, rheumatoid arthritis, smoking, and alcohol intake). Among adults aged 50 and over, elevated probabilities were defined as 3% or greater for hip fracture and 20% or greater for major osteoporotic fracture. RESULTS: Mean skew-adjusted fracture probabilities were 0.5% for hip fracture and 5.3% for major osteoporotic fracture among adults aged 40 and over, and 0.9% and 7.4%, respectively, among adults aged 50 and over. The percentages of adults aged 50 and over with an elevated hip or major osteoporotic fracture probability were 19% and 8%, respectively. Fracture probabilities varied significantly by age (older groups had higher probabilities than younger groups), sex (women had higher probabilities than men), and race and Hispanic origin (non-Hispanic white persons had higher probabilities than all other race and Hispanic groups) (p < 0.001). An estimated 95%-97% of adults aged 50 and over with an elevated probability of either fracture type had femoral neck osteoporosis or low bone mass. CONCLUSIONS: Mean hip and major osteoporotic fracture probabilities were 0.5% and 5.3%, respectively, for adults aged 40 and over. Among adults aged 50 and over, mean hip and major osteoporotic fracture probabilities were 0.9% (19% with elevated values) and 7.4% (8% with elevated values), respectively.
27658548 PTPN2-deficiency exacerbates T follicular helper cell and B cell responses and promotes th 2017 Jan Non-coding single nucleotide polymorphisms that repress PTPN2 expression have been linked with the development of type 1 diabetes, rheumatoid arthritis and Crohn's disease. PTPN2 attenuates CD8(+) T cell responses to self and prevents overt autoreactivity in the context of T cell homeostasis and antigen cross-presentation. The role of PTPN2 in other immune subsets in the development of autoimmunity remains unclear. Here we show that the inducible deletion of PTPN2 in hematopoietic compartment of adult non-autoimmune prone mice results in systemic inflammation and autoimmunity. PTPN2-deficient mice had increased inflammatory monocytes, B cells and effector T cells in lymphoid and non-lymphoid tissues and exhibited symptoms of dermatitis, glomerulonephritis, pancreatitis and overt liver disease. Autoimmunity was characterised by the formation of germinal centers in the spleen and associated with markedly increased germinal center B cells and T follicular helper (T(fh)) cells and circulating anti-nuclear antibodies, inflammatory cytokines and immunoglobulins. CD8(+) T cell proliferative responses were enhanced, and interleukin-21-induced STAT-3 signalling in T(fh) cells and B cells was increased and accompanied by enhanced B cell proliferation ex vivo. These results indicate that deficiencies in PTPN2 across multiple immune lineages, including naive T cells, T(fh) cells and B cells, contribute to the development of autoimmunity.
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.
29164284 Uncommon observation of bifocal giant subchondral cysts in the hip: diagnostic role of CT 2018 Apr Subchondral cysts (or geodes) are common in osteoarthritis (OA), usually in association with other typical signs, i.e., joint space narrowing, subchondral bone sclerosis, and osteophytosis. However, large lesions without the typical signs of OA or lesions located outside the weight-bearing areas are unusual and may be confused for other conditions, in particular, those of tumoral origin. We report the findings in a 48-year-old man who had been complaining of left buttock pain for 3 years, getting worse over the last year, and an evolutive limited range of motion of the hip. The pain was increased by weight-bearing and was not relieved by nonsteroidal anti-inflammatory drugs. Radiographs and CT showed a large multilocular lytic lesion within the femoral head and a large lytic lesion in the left ilio-ischiatic ramus, raising the question of bifocal tumoral involvement. On MRI, the lesions had low signal intensity on T1- and high signal intensity on T2-weighted MR images, with subtle peripheral enhancement on post-contrast T1-weighted images. CT arthrography, by demonstrating a communication between the femoral head and ischiatic cysts and the joint space allowed us to definitively rule out malignant conditions and to make the diagnosis of subchondral bone cysts. Total hip arthroplasty was performed. Pathological analysis of the resected femoral head and of material obtained at curettage of the ischiatic lesion confirmed the diagnosis of degenerative geodes. This case illustrates an atypical bifocal location of giant subchondral cysts in the hip joint mimicking lytic tumors, in the absence of osteoarthritis or rheumatoid arthritis, and highlights the role of CT arthrography in identifying this condition.
29063666 Dimethyl fumarate inhibits osteoclasts via attenuation of reactive oxygen species signalli 2018 Feb Bone destructive diseases are common worldwide and are caused by dysregulation of osteoclast formation and activation. During osteoclastogenesis, reactive oxygen species (ROS) play a role in the intracellular signalling triggered by receptor activator of nuclear factor-κB ligand (RANKL) stimulation. Previously, we demonstrated that induction of antioxidant enzymes by Nrf2 activation using Nrf2-gene transfer, an ETGE-peptide or polyphenols, successfully ameliorated RANKL-dependent osteoclastogenesis. Dimethyl fumarate (DMF) has been shown to activate Nrf2 signalling and has been lately used in clinical trials for neurodegenerative diseases. In this study, we hypothesized that Nrf2 activation by DMF would inhibit osteoclastogenesis and bone destruction via attenuation of intracellular ROS signalling through antioxidant mechanisms. RAW 264.7 cells were used as osteoclast progenitor cells. We found that DMF induced Nrf2 translocation to the nucleus, augmented Nrf2 promoter-luciferase reporter activity and increased antioxidant enzyme expression. Using flow cytometry, we found that DMF attenuated RANKL-mediated intracellular ROS generation, which resulted in the inhibition of RANKL-mediated osteoclastogenesis. Local DMF injection into the calvaria of male BALB/c mice resulted in attenuated bone destruction in lipopolysaccharide-treated mice. In conclusion, we demonstrated in a preclinical setting that DMF inhibited RANKL-mediated osteoclastogenesis and bone destruction via induction of Nrf2-mediated transcription of antioxidant genes and consequent decrease in intracellular ROS levels. Our results suggest that DMF may be a promising inhibitor of bone destruction in diseases like periodontitis, rheumatoid arthritis and osteoporosis.
30603535 Substance-P Ameliorates Dextran Sodium Sulfate-Induced Intestinal Damage by Preserving Tis 2018 Feb Intestinal inflammation alters immune responses in the mucosa and destroys colon architecture, leading to serious diseases such as inflammatory bowel disease. Thus, the modulation of intestinal integrity and immune responses in IBD can be the critical factor to be considered to reduce the severity of damages. Substance-P (SP), endogenous peptide to be involved in cell proliferation, migration and immune modulation, can exert the therapeutic effect on diverse diseases including cornea damage, rheumatoid arthritis and diabetic complications. SP was found to elevate expression of junctional molecule. Considering the function of SP reported previously, it was inferred that SP is capable of exert the beneficial effect of SP on intestinal diseases by controlling intestinal structure as well as immune responses. In this study, we explored the therapeutic effect of SP on dextran sodium sulfate-induced intestine damage by injecting SP. The effects of SP were evaluated by analyzing crypt structures, proliferating cell pool and infiltration of immune cells. DSS treatment provoked abnormal immune response and disruption of intestine epithelial barrier. However, co-treatment of SP obviously blocked the development of intestinal damages by declining inflammatory responses and sustaining intestinal structure more intact. The treatment of SP to chronic damages also promoted intestinal regeneration by preserving the integrity of colon tissue. Moreover, DSS-induced reduction of epithelial junctional molecule was obviously inhibited by SP treatment in vitro. Taken together, our data indicate that SP can reduce intestinal damages, possibly by modulating barrier structure and immune response. Our results propose SP as candidate therapeutics in intestinal damages.
28839360 Prim-O-glucosylcimifugin Attenuates Lipopolysaccharideinduced Inflammatory Response in RAW 2017 Jul BACKGROUND: Radix Saposhnikoviae (RS) exerts anti-inflammatory, analgesic, antipyretic, antioxidation effects and has been used in traditional Chinese medicine to treat common colds, headache, and rheumatoid arthritis. Prim-O-glucosylcimifugin (POG) is the highest content chromone and one of the major active constituents in RS. OBJECTIVE: The study was aimed to explore the anti-inflammation effects of POG in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. MATERIALS AND METHODS: Cell viability was detected by Cell Counting Kit-8 assay. Production of nitric oxide (NO), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and IL-6 was assessed by enzyme-linked immunosorbent assay. Real-time polymerase chain reaction and Western blot were performed to analyze mRNA and protein levels, respectively. RESULTS: During the whole experiment, 15, 50, and 100 μg/mL of POG had no cytotoxicity on RAW 264.7 cells. POG dose-dependently inhibited the production of NO, TNF-α, IL-1β, and IL-6 that were induced by LPS. POG treatment downregulated the mRNA and protein expression inducible NO synthase (iNOS) and cyclooxygenase 2 (COX-2) in LPS-activated RAW 264.7 macrophages in a concentration-dependent manner. Furthermore, LPS-induced JAK2/STAT3 activation was prevented in RAW 264.7 macrophages by POG treatment. STAT3 overexpression significantly reversed the effects of POG on LPS-activated RAW 264.7 macrophages. CONCLUSION: These results demonstrate that POG exerts anti-inflammatory effects through the inhibition of iNOS and COX-2 expression by inhibiting the phosphorylation of JAK2/STAT3. SUMMARY: POG exerts anti-inflammatory effects in RAW 264.7 macrophages through the inhibition of iNOS and COX-2 expression by inhibiting JAK2/STAT3 signaling. Abbreviations used: LPS: Lipopolyssacharide; NO: Nitric oxide; TNF-α: Tumor necrosis factor-α; IL: Interleukin; RS: Radix Saposhnikoviae; POG: Prim-O-glucosylcimifugin; iNOS: Inducible NO synthase; COX2: Cyclooxygenase; FBS: Fetal bovine serum; DMSO: Dimethylsulfoxide; CCK-8: Cell Counting Kit; RIPA: Radio immunoprecipitation assay buffer; ECL: Enhanced chemiluminescence; SD: Standard deviation; ELISA: Enzyme-Linked immunosorbent assay.
28723711 Epidemiology of autoimmune and inflammatory diseases in a French nationwide HIV cohort. 2017 Sep 24 BACKGROUND: HIV infection and inflammatory and autoimmune diseases (IADs) are both related to immune dysfunction. Epidemiological data on IAD in patients living with HIV (PLHIV) are scarce. The aim of this study was thus to estimate the prevalence of 26 IAD among PLHIV followed in a large French multicenter cohort in the combination antiretroviral therapy (cART) era (from January 2000 to July 2013), and to describe their occurrence according to cART onset, the immuno-virological status of patients and hepatitis C virus (HCV) and/or hepatitis B virus coinfection. METHOD AND RESULTS: During the study period, 33 403 PLHIV were included in the Dat'AIDS cohort; 1381 patients with an IAD were identified. The most prevalent IADs were psoriasis, sarcoidosis, rheumatoid arthritis, ankylosing spondyloarthritis, Grave's disease, autoimmune hemolytic anemia, immune thrombocytopenia and chronic inflammatory bowel disease. In contrast, the prevalence of systemic lupus erythematosus and multiple sclerosis were low. Most patients (59%) developed IAD after HIV infection with a mean delay of 10.6 ± 6.4 years. Compared with the entire cohort, HCV coinfection was significantly more frequent in patients with psoriasis, Grave's disease and immune thrombocytopenia, and chronic hepatitis B in patients was more frequent in those with immune thrombocytopenia and autoimmune hemolytic anemia. Among patients developing IAD after the diagnosis of HIV infection, 572 (70%) were on antiretroviral therapy and 419 of them (73%) had undetectable HIV viral load. CONCLUSION: Our study showed that some IAD are not rare among PLHIV and occur mostly in patients with immuno-virological control under cART. The higher frequency of HCV or hepatitis B virus coinfection for some IAD is also confirmed.
28620373 Mechanisms of Autoantibody-Induced Pathology. 2017 Autoantibodies are frequently observed in healthy individuals. In a minority of these individuals, they lead to manifestation of autoimmune diseases, such as rheumatoid arthritis or Graves' disease. Overall, more than 2.5% of the population is affected by autoantibody-driven autoimmune disease. Pathways leading to autoantibody-induced pathology greatly differ among different diseases, and autoantibodies directed against the same antigen, depending on the targeted epitope, can have diverse effects. To foster knowledge in autoantibody-induced pathology and to encourage development of urgently needed novel therapeutic strategies, we here categorized autoantibodies according to their effects. According to our algorithm, autoantibodies can be classified into the following categories: (1) mimic receptor stimulation, (2) blocking of neural transmission, (3) induction of altered signaling, triggering uncontrolled (4) microthrombosis, (5) cell lysis, (6) neutrophil activation, and (7) induction of inflammation. These mechanisms in relation to disease, as well as principles of autoantibody generation and detection, are reviewed herein.
28347505 Complexity Assessed by the INTERMED in Patients With Somatic Symptom Disorder Visiting a S 2017 Jul BACKGROUND: Somatic symptom disorders (SSD), a new classification in the Diagnostic and Statistical Manual of Mental Disorders, fifth edition is associated with problematic diagnostic procedures and treatment that lead to complex care. In somatic health care, the INTERMED has been used to assess levels of complexity; however, in SSD this instrument has not yet been applied. OBJECTIVE: This study aims to explore complexity in patients with SSD using the INTERMED, hereby contributing to an increased comprehension of this new patient group. METHOD: In this cross-sectional study, the INTERMED was used to assess complexity in outpatients with SSD at the Clinical Centre of Excellence for Body, Mind, and Health (The Netherlands), along biologic, psychologic, social, and health care domains. This was done retrospectively with patient files from consecutive patients from 2011 until 2015. RESULTS: In the total SSD sample (N = 187), 63% was female, the mean age (standard deviation) was 42 (±12.4) years, with an average educational level. The mean INTERMED score was 23.5 indicating high overall complexity in this population. A high proportion of our sample (69%) scored as highly complex (>20). High complexity was associated with higher depression and anxiety scores, but not with a higher number of physical symptoms. CONCLUSIONS: This study demonstrates that patients with SSD form a high-complex group, with higher scores compared with literature about multiple sclerosis, rheumatoid arthritis, or patient waiting for a liver transplant. INTERMED outcomes indicate a need for extensive diagnostic procedures and integrated multidisciplinary care for patients with SSD. Attention should especially be paid to mental disorders (depression and anxiety), given their association with high complexity.
28092324 Long-term use of opioids for nonmalignant pain among community-dwelling persons with and w 2017 Feb Persons with Alzheimer disease (AD) commonly present with chronic nonmalignant pain, but long-term use of opioids among this population has not been studied previously. Our aim was to investigate the prevalence of long-term (≥180 days) use of opioids for nonmalignant pain and associated factors among community-dwelling persons with AD and to compare the prevalence with a matched cohort without AD. The Medication use and Alzheimer's disease (MEDALZ) cohort was used for this study, comprising all community-dwelling persons diagnosed with AD in Finland during 2005 to 2011 and their matched comparison persons without AD. After exclusion of persons with active cancer treatment, 62,074 persons with and 62,074 persons without AD were included in this study. Data were collected from nationwide registers. Opioids were used by 13,111 persons with and by 16,659 without AD. Overall long-term opioid use was more common among persons without AD (8.7%) than among persons with AD (7.2%, P < 0.0001). However, among opioid users, prevalence of long-term opioid use was slightly higher among persons with AD than among those without AD (34.2% vs 32.3%, respectively, P = 0.0004). Long-term use of transdermal opioids was more than 2-fold among opioid users with AD (13.2%) compared with users without AD (5.5%). Factors associated with long-term opioid use included AD, age ≥80 years, female sex, rheumatoid arthritis, osteoporosis, low socioeconomic position, history of substance abuse, and long-term benzodiazepine use. Prevalence of long-term opioid use was somewhat similar among both groups. Among persons with AD, long-term opioid use was strongly associated with transdermal opioids.
28065772 Multimorbidity in Middle-Aged Adults with Cerebral Palsy. 2017 Jun OBJECTIVE: Individuals with cerebral palsy have less lean body mass, greater relative adiposity, and lower fitness and physical activity participation, and yet the prevalence of age-related multimorbidity in this population has yet to be established. The study objective was to examine the prevalence of lifestyle-related chronic conditions and multimorbidity in a sample of middle-aged adults with cerebral palsy. METHODS: A clinic-based sample of middle-aged adults with cerebral palsy was examined using Electronic Medical Records Search Engine software. Our cohort included 435 individuals aged 40 to 60 years, with an International Classification of Diseases, Clinical Modification, 9th and 10th Revisions Diagnosis Code for cerebral palsy. Prevalence of 12 chronic conditions was evaluated, including existing diagnoses or historical record of osteopenia/osteoporosis, myocardial infarction, stroke, coronary artery disease, impaired glucose tolerance/type 2 diabetes, other cardiovascular conditions, rheumatoid arthritis, osteoarthritis, asthma, emphysema, prehypertension/hypertension, and hyperlipidemia. Multivariate logistic models were used to estimate multimorbidity (ie, ≥2 chronic conditions), adjusting for age, sex, smoking status, obesity, and Gross Motor Function Classification System (GMFCS). RESULTS: There were 137 unique multimorbidity combinations. Multimorbidity was significantly more prevalent among obese versus nonobese individuals for both GMFCS I-III (75.8% vs 53.6%) and GMFCS IV-V (79.0% vs 64.2%), but was also significantly higher in nonobese individuals with GMFCS IV-V (64.2%) compared with nonobese individuals with GMFCS I-III (53.6%). Both the obesity status (odds ratio, 2.20; 95% confidence interval, 1.32-2.79) and the GMFCS IV-V category (odds ratio, 1.81; 95% confidence interval, 1.32-3.68) were independently associated with multimorbidity. CONCLUSIONS: Middle-aged adults with cerebral palsy have high estimates of multimorbidity; both obesity and higher GMFCS levels are independently associated with greater risk.
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.
29190740 Correlation of serum cytokines, chemokines, growth factors and enzymes with periodontal di 2017 BACKGROUND: Periodontal disease (PD) is characterized by inflammatory tissue destruction in tooth supporting apparatus. Many studies indicate that the underlying pathogenesis is in concordance with rheumatoid arthritis (RA) sharing immune-inflammatory events affect both diseases. The aim of this study was to investigate serum cytokines, chemokines, growth factors, enzymes and costimulatory proteins in association with periodontal conditions in PD and RA subjects. MATERIALS & METHODS: Periodontal examination was performed in RA (n = 38), PD (n = 38) and healthy subjects (n = 14). Bleeding on probing (BOP) and probing pocket depth (PPD) were measured. Marginal bone loss (MBL) for premolars and molars was measured on digital panoramic radiographs. PD was defined as present if the PPD was ≥5mm in ≥ 3 different sites. Serum samples were collected from all subjects. A multiplex proximity extension assay (PEA) was used to analyze the samples for simultaneous measurement of 92 cytokines. Cytokines with ≥ 60% quantitative results were included. RESULTS: A significant positive correlation was seen for ST1A1, FGF-19 and NT-3 whereas EN-RAGE, DNER, CX3CL1 and TWEAK associated inversely with BOP, PPD≥ 5mm and MBL but positively with number of teeth. Several CD markers (CD244, CD40, CDCP1, LIF-R, IL-10RA, CD5 and CD6) were found to be associated with BOP, shallow and deep pockets, MBL and number of teeth, either directly or inversely. Most chemokines (CCL8, CX3CL1, CXCL10, CXCL11, CCL11, CCL4, CCL20, CXCL5, CXCL6, and CCL23) were positively associated with number of teeth and some inversely related to MBL (CCL8, CXCL10). Proteins with enzymatic activity (ST1A1, HGF and CASP-8) were directly related to the severity of periodontal conditions and inversely related to number of teeth. Aside from FGF-19, other growth factors were also directly associated with MBL (HGF), number of teeth (VEGF-A, LAP TGF-beta-1) and, inversely to, shallow pockets (LAP TGF-beta-1, TGFA and Beta-NGF). Out of 33 cytokines, 32 associated inversely with shallow pockets, whereas only CD40 associated positively. Associations between cytokines and periodontal parameters in the RA group were comparatively less. Statistical analyses were adjusted for multivariate effects using the Benjamini-Hochberg false discovery rate method. CONCLUSION: Systemic inflammatory burden, via known and novel markers, is associated with periodontal conditions in PD and RA subjects. Shallow pockets are not associated with a higher inflammatory state.