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Abstract This study examined the associations between tobacco smoking and serum cotinine levels, an objective biochemical measure of tobacco smoke exposure, with markers of inflammation, i.e., interferon-gamma (IFN-γ), interleukin 10 (IL-10), interleukin 2 (IL-2) and tumour necrosis factor-alpha (TNF-α) in people living with HIV (PLWH).These specific markers were selected because of their hypothesised associations with smoking, PLWH and their outcomes. In a random sample of ≥ 18-year-old PLWH receiving care at 17 public healthcare facilities across the Western Cape Province in South Africa, data collection included self-reported smoking history, and serum levels of cotinine and selected inflammatory markers. The inflammatory marker data were log transformed because of the skewedness of their distribution. Linear regression models (1) adjusted for age and gender, and (2) fully adjusted for age, gender, current alcohol use, body mass index and CD4 counts were used to examine the associations between smoking tobacco or serum cotinine and inflammatory markers. Level of significance was p

Aim Methods Results Conclusions Epigenetic regulation of the key inflammatory genes plays a crucial role in controlling monocyte/macrophage‐mediated local and systemic responses to bacterial challenges. However, it has not been addressed in apical periodontitis (AP). We aimed to explore the methylation pattern of the TNF‐α gene promoter and its association with the inflammatory phenotype of peripheral blood monocytes from individuals with AP and controls.A cross‐sectional study was conducted, including otherwise healthy individuals with AP (n = 25) and controls (n = 29). Monocytes were isolated from the volunteer’s blood samples using a Ficoll gradient followed by negative immunoselection. RNA and DNA were extracted. The DNA methylation profiles of the TNF‐α gene promoter region were analyzed using bisulfite sequencing PCR. The mRNA expression levels of DNA methyltransferases 3a (DNMT3a) and Ten Eleven Translocation enzymes 1(TET1) were assessed by qPCR. A fraction of primary monocytes was also cultured for 24 h, and the supernatant was collected to measure cytokine levels through a Luminex assay. Generalized structural equation models (GSEM) evaluated the association between AP, DNA methylation, and TNF‐α protein expression controlled for potential covariates. Models included the effect of the methylation of TNF‐α gene promoter as a mediator of the association between AP and TNF‐α protein expression levels.Monocytes from AP individuals exhibited a heightened secretion of TNF‐α and IL‐1β and hypomethylation of the TNF gene promoter (p < .05). AP diagnosis was associated with the TNF‐α gene promoter´s hypomethylated profile and enhanced pro‐inflammatory cytokine levels, while lower methylation of the gene promoter region and ‐163 CpG single site mediated TNF‐α overexpression (p < .05).DNA hypomethylation at the TNF‐α gene mediates a proinflammatory phenotype in monocytes from AP patients, supporting a role in the systemic response. [ABSTRACT FROM AUTHOR]

While the exercise-induced responses of circulated biomarkers related to inflammation and brain health are well documented in humans, little is known about the effect of menopausal status on these responses. This study compared the responses of inflammatory cytokines and brain-derived neurotrophic factor (BDNF) to high-intensity exercise between pre- and postmenopausal middle-aged females. Eight premenopausal (44 ± 3 years) and seven postmenopausal (57 ± 2 years) females performed a high-intensity interval training (HIIT) session consisting of 10 × 1 min running intervals (90% maximum heart rate) separated by 1 min passive recovery intervals. Blood samples were collected at baseline (fasted), pre-exercise (postprandial), and at 0, 30, and 90 min post-HIIT and analyzed for interleukin (IL-6) and 10 (IL-10), tumour necrosis factor-alpha (TNF-α), and BDNF. IL-6 significantly increased from pre-exercise to 0 min post-HIIT in postmenopausal (+40%, p = 0.01) and to 30 min post-HIIT in premenopausal females (+60%, p = 0.02). IL-6 remained elevated at 90 min post-HIIT in premenopausal (+104%, p = 0.05) and to a higher degree in postmenopausal females (+385%, p < 0.001). IL-10 showed no response. TNF-α increased from pre- to 0 min post-HIIT (+10%, p = 0.05), then decreased to below pre-exercise at 30 min (−10%, p = 0.02) and 90 min (−5%, p = 0.04) in both groups. BDNF increased immediately post-HIIT in premenopausal (+60%, p < 0.001) but not postmenopausal females. The differences in IL-6 and BDNF responses to HIIT between pre- and postmenopausal females provide evidence of the role of female reproductive hormones in the regulation of these exercise-induced responses.

While the exercise-induced responses of circulated biomarkers related to inflammation and brain health are well documented in humans, little is known about the effect of menopausal status on these responses. This study compared the responses of inflammatory cytokines and brain-derived neurotrophic factor (BDNF) to high-intensity exercise between pre- and postmenopausal middle-aged females. Eight premenopausal (44 ± 3 years) and seven postmenopausal (57 ± 2 years) females performed a high-intensity interval training (HIIT) session consisting of 10 × 1 min running intervals (90% maximum heart rate) separated by 1 min passive recovery intervals. Blood samples were collected at baseline (fasted), pre-exercise (postprandial), and at 0, 30, and 90 min post-HIIT and analyzed for interleukin (IL-6) and 10 (IL-10), tumour necrosis factor-alpha (TNF-α), and BDNF. IL-6 significantly increased from pre-exercise to 0 min post-HIIT in postmenopausal (+40%, p = 0.01) and to 30 min post-HIIT in premenopausal females (+60%, p = 0.02). IL-6 remained elevated at 90 min post-HIIT in premenopausal (+104%, p = 0.05) and to a higher degree in postmenopausal females (+385%, p < 0.001). IL-10 showed no response. TNF-α increased from pre- to 0 min post-HIIT (+10%, p = 0.05), then decreased to below pre-exercise at 30 min (−10%, p = 0.02) and 90 min (−5%, p = 0.04) in both groups. BDNF increased immediately post-HIIT in premenopausal (+60%, p < 0.001) but not postmenopausal females. The differences in IL-6 and BDNF responses to HIIT between pre- and postmenopausal females provide evidence of the role of female reproductive hormones in the regulation of these exercise-induced responses. [ABSTRACT FROM AUTHOR]

One of the adverse effects of the antineoplastic drug cisplatin (CS) is damage to testicular tissue. This study aimed to examine the potential therapeutic effect of thymoquinone (TQ), a strong antioxidant, against testicular damage caused by CS. In the experiment, 28 rats were used, and the rats were randomly divided into four groups: control (n = 7), CS (n = 7), CS + TQ (n = 7), and TQ (n = 7). The experiment was called off after all treatments were finished on day 15. Blood serum and testicular tissues were utilized for biochemical, histological, immunohistochemical, mRNA expression, and gene protein investigations. The testosterone level decreased and oxidative stress, histopathological damage, dysregulation in mitochondrial dynamics, inflammation and apoptotic cells increased in testicular tissue due to CS administration. TQ supplementation showed anti-inflammatory, antioxidant, and anti-apoptotic effects in response to CS-induced testicular damage. In addition, TQ contributed to the reduction of CS-induced toxic effects by regulating the TNF-α/OTULIN/NF-κB pathway. TQ supplementation may be a potential therapeutic strategy against CS-induced testicular damage by regulating the TNF-α/OTULIN/NF-κB axis, inhibiting inflammation, oxidative stress, and apoptosis. [ABSTRACT FROM AUTHOR]

Objective: To determine the dynamics of serum levels of TNF-α in patients with juvenile idiopathic arthritis (JIA) treated with anti-TNF-α biological drugs and investigate their association with the disease activity. Methods: We conducted a single-centre, observational cohort study in 98 patients with JIA (30 boys, 68 girls, mean age 11.3 years) treated with anti-TNF-α biological drugs. Clinical examinations and laboratory assessments of serum levels of TNF-α were performed before starting therapy with biological drug and at 6-month intervals afterwards up to 2.5 years. Results: The analysis of serum levels of TNF-α in relation to the disease activity states showed the highest mean serum levels of TNF-α in patients on etanercept who had low disease activity states and in patients on adalimumab who had inactive disease. The correlation analysis in patients with JIA treated with etanercept or adalimumab showed a weak negative correlation between the serum levels of TNF-α and JADAS10 scores (p = 0.007), (r = − 0.177). Conclusion: The assessment of serum levels of TNF-α in children with JIA during treatment with etanercept or adalimumab is not a reliable biomarker of disease activity or immunological remission. Longitudinal measurement of TNF-α has no added clinical value in patients with JIA treated with anti-TNF-α biological drugs. Key Points • There is limited evidence regarding the effect of anti-TNF therapy on serum concentrations of TNF-α in patients with juvenile idiopathic arthritis • Our study showed an increase in the serum level of TNF-α after the initiation of therapy with either etanercept or adalimumab, which was more significant in patients with inactive or low disease activity • Serum TNF-α is most likely not biologically active during therapy with TNF-α inhibitors and therefore not a reliable biomarker of disease activity or immunological remission in patients with juvenile idiopathic arthritis [ABSTRACT FROM AUTHOR]

Introduction: Various studies have evaluated the in vitro anti-inflammatory effect of nitazoxanide (NTZ), suggesting new therapeutic functions for this drug. Aims: To evaluate the in vivo anti-inflammatory and antinociceptive activities of NTZ in acute mice models. Methods: Mice models of paw oedema, abdominal writhing, formalin and the rota-rod test were used. Results: Oral treatment with NTZ induced inhibition of paw oedema (60.00% and 66.67% at doses of 10 and 30 mg/kg, respectively) in the first hour after inflammatory stimulus, carrageenan (Cg). There was also a significant inhibition of 60.71% and 40.00% at the 30 mg/kg dose after 4h and 6 h, respectively after inflammation. Four hours after inflammation, the histological analysis of the footpad of animals treated with 30 mg/kg of NTZ showed a reduction in the migration of inflammatory cells by 65.77%. It is also important to highlight that there was a significant reduction of tumor necrose factor-alfa (TNF-a) in the initial phase of inflammation, 2 h after administration of the Cg. There was an inhibition in abdominal contortions by 54.14% and 56.21% at 30 and 90 mg/kg doses, respectively. In the formalin test only the dose of 90 mg/kg showed antinociceptive action (54.85%; first phase and 45.67%; second phase). The results from rota-rod test showed that motor coordination was not affected with NTZ. Conclusions: This anti-inflammatory activity of NTZ appears to be a consequence of its ability to reduce the levels of an important mediator of the inflammatory response and pain the TNF-a. [ABSTRACT FROM AUTHOR]

Background Desquamative gingivitis (DG) is a non-plaque induced gingival disease. Clinical examination coupled with histopathological and immunofluorescence studies diagnose it, however, diagnosis of about one-third of DG cases is still elusive which leads to poor clinical outcomes. Therefore, biomarker profiling of DG will help in predicting better treatment outcomes. The objective of the study was to evaluate the salivary TNF-a as a biomarker of DG and compare it with chronic gingivitis (CG) and clinically healthy (CH) subjects. Materials and Methods A case-control study was done with 94 subjects having; DG (n=31), chronic gingivitis CG (n=31), and clinically healthy CH (n=32) were recruited in the study after they fulfilled subject selection criteria and signed the consent form. Detailed history and clinical examination were done. Subjects were told to abstain from eating 2 hours before saliva collection. Three ml of saliva was collected in the saliva collection tubes between 9 AM to 12 PM. The collected samples were stored at -80 centigrade and TNF-a levels were assessed employing an ELISA technique (R&D systems). The data were analyzed using SPSS (Version 20, IBM, USA) statistical software. Results Salivary TNF-a levels were significantly increased in DG (33.71±12.15 pg/ml,) as compared to CH (5.99±2.11) and CG (13.48±1.16 pg/ml) subjects. The receiver operating curve (ROC) of DG for salivary TNF-a biomarker showed an area under the curve (AUC) of 0.973. Conclusion Salivary TNF-a is a good diagnostic biomarker that is significantly increased in desquamative gingivitis. [ABSTRACT FROM AUTHOR]

Background & aimsThe stimulator of interferon genes (STING)/TANK-binding kinase 1 (TBK1) pathway is vital in mediating innate immune and inflammatory responses during oxidative/endoplasmic reticulum (ER) stress. However, it remains unknown whether macrophage thioredoxin-interacting protein (TXNIP) may regulate TBK1 function and cell death pathways during oxidative/ER stress.MethodsA mouse model of hepatic ischaemia/reperfusion injury (IRI), the primary hepatocytes, and bone marrow-derived macrophages were used in the myeloid-specific TXNIP knockout (TXNIPM-KO) and TXNIP-proficient (TXNIPFL/FL) mice.ResultsThe TXNIPM-KO mice were resistant to ischaemia/reperfusion (IR) stress-induced liver damage with reduced serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST) levels, macrophage/neutrophil infiltration, and pro-inflammatory mediators compared with the TXNIPFL/FL controls. IR stress increased TXNIP, p-STING, and p-TBK1 expression in ischaemic livers. However, TXNIPM-KO inhibited STING, TBK1, interferon regulatory factor 3 (IRF3), and NF-κB activation with interferon-β (IFN-β) expression. Interestingly, TXNIPM-KO augmented nuclear factor (erythroid-derived 2)-like 2 (NRF2) activity, increased antioxidant gene expression, and reduced macrophage reactive oxygen species (ROS) production and hepatic apoptosis/necroptosis in IR-stressed livers. Mechanistically, macrophage TXNIP deficiency promoted cylindromatosis (CYLD), which colocalised and interacted with NADPH oxidase 4 (NOX4) to enhance NRF2 activity by deubiquitinating NOX4. Disruption of macrophage NRF2 or its target gene 2',5' oligoadenylate synthetase-like 1 (OASL1) enhanced Ras GTPase-activating protein-binding protein 1 (G3BP1) and TBK1-mediated inflammatory response. Notably, macrophage OASL1 deficiency induced hepatocyte apoptotic peptidase activating factor 1 (APAF1), cytochrome c, and caspase-9 activation, leading to increased caspase-3-initiated apoptosis and receptor-interacting serine/threonine-protein kinase 3 (RIPK3)-mediated necroptosis.ConclusionsMacrophage TXNIP deficiency enhances CYLD activity and activates the NRF2-OASL1 signalling, controlling IR stress-induced liver injury. The target gene OASL1 regulated by NRF2 is crucial for modulating STING-mediated TBK1 activation and Apaf1/cytochrome c/caspase-9-triggered apoptotic/necroptotic cell death pathway. Our findings underscore a novel role of macrophage TXNIP-mediated CYLD-NRF2-OASL1 axis in stress-induced liver inflammation and cell death, implying the potential therapeutic targets in liver inflammatory diseases.Lay summaryLiver inflammation and injury induced by ischaemia and reperfusion (the absence of blood flow to the liver tissue followed by the resupply of blood) is a significant cause of hepatic dysfunction and failure following liver transplantation, resection, and haemorrhagic shock. Herein, we uncover an underlying mechanism that contributes to liver inflammation and cell death in this setting and could be a therapeutic target in stress-induced liver inflammatory injury.

AbstractRespiratory tract infections are a common cause of morbidity and mortality globally. The current paper aims to treat this respiratory disorder. Therefore, we elucidated the phytochemical profile of Euphorbia milii flowers and isolated chlorogenic acid (CGA) for the first time. The electrospraying technique was utilized to prepare CGA nanoparticles in polyvinyl alcohol (PVA)/PLGA polymeric matrix. Complete in vitro characterizations were performed to determine particle size, polydispersity index (PDI), zeta potential, loading efficiency (LE), scanning electron microscopy and in vitro release study. The optimum formula (F2) with a particle size (454.36 ± 36.74 nm), a surface charge (–4.56 ± 0.84 mV), % of LE (80.23 ± 5.74), an initial burst (29.46 ± 4.79) and % cumulative release (97.42 ± 4.72) were chosen for further activities. In the murine lung infection model, PVA/PLGA NPs loaded with CGA (F2) demonstrated in vivo antibacterial activity against Pseudomonas aeruginosa. Using a plaque assay, the in vitro antiviral activity was investigated. The F2 exhibited antiviral activity against coronavirus (HCoV-229E) and (Middle East respiratory syndrome coronavirus (MERS-CoV), NRCEHKU270). The IC50 of F2 against HCoV-229E and MERS-CoV was 170 ± 1.1 and 223 ± 0.88 µg/mL, respectively. The values of IC50 of F2 were significantly lower (p

Studies involving the immune response in Chagas disease suggest an imbalance in the immune response of symptomatic patients, with an inflammatory profile dominating in Chagas heart disease, mainly by tumour necrosis factor (TNF). TNF is considered a key cytokine in immunopathology in chronic carriers in several processes during the immune response. Our work aimed to evaluate regulatory (interleukin [IL]‐4 and IL‐10) and inflammatory (TNF, interferon‐gamma [IFN‐γ], IL‐2 and IL‐6) cytokines in peripheral blood mononuclear cells culture supernatants. of affected patients with undetermined clinical forms—IND (n = 13) mild heart form—CARD1 (n = 13) and severe cardiac form—CARD2 (n = 16), treated in vitro with two TNF blockers, Adalimumab (ADA) and Etanercept (ETA) alone or in association with Benznidazole (BZ). The results indicate that ADA was more competent in blocking TNF (compared to ETA) in all groups but with much lower levels in the CARD2 group. ETA statistically decreased TNF levels only in the CARD2 group. IFN‐γ increased in the CARD2 group after treatment with ETA relative to ADA. IL‐4 had its levels decreased when treated by both drugs. IL‐2 was detected in cells from CARD2 carriers compared to the NEG group after treatment with both drugs. The association with BZ decreased levels of IL‐2/TNF and increased IL‐4. These data reinforce the participation of TNF in severe Chagas heart disease and bring perspectives on using these blockers in the immunological treatment of Chagas disease since the use of BZ is extremely limited in these patients. [ABSTRACT FROM AUTHOR]

A systematic review and meta-analysis in the Journal of Nutritional Science examined the impact of chia seed supplementation on inflammatory biomarkers, focusing on CRP, IL-6, and TNF-α. The study, involving 210 participants across four randomized controlled trials, found that chia consumption led to a significant decrease in CRP levels but did not affect IL-6 and TNF-α. The document also explores the use of chia seeds in managing overweight and obese individuals with type 2 diabetes, with mixed results on cardiovascular risk factors and weight loss. Additionally, it discusses the nutritional benefits of chia seeds, emphasizing their potential as a source of proteins and bioactive peptides with health advantages. [Extracted from the article]

Renal sinus fat (RSF) crucially influences metabolic regulation, inflammation, and vascular function. We investigated the association between RSF accumulation, metabolic disorders, and nutritional status in obese individuals with hypertension. A cross-sectional study involved 51 obese hypertensive patients from Salamat Specialized Community Clinic (February–September 2022). Basic and clinical information were collected through interviews. Data included anthropometrics, blood pressure, number of antihypertensive medications, body composition (bioelectrical impedance analysis), dietary intake (semi-quantitative 147-item food frequency questionnaire), and blood samples. Renal sinus fat was measured via ultrasonography. Statistical analyses included Pearson correlation, binary logistic regression, and linear regression. RSF positively correlated with abdominal visceral adipose tissue (VAT) area (P = 0.016), systolic blood pressure (SBP) (P = 0.004), and diastolic blood pressure (DBP) (P = 0.005). A strong trend toward a positive association was observed between antihypertensive medications and RSF (P = 0.062). In linear regression, RSF was independently associated with abdominal VAT area, SBP, and DBP after adjusting for confounders. After considering other risk factors, RSF volume relates to prescribed antihypertensive medications, hypertension, and central fat accumulation in obese hypertensive subjects. These findings suggest the need for further investigations into whether RSF promotes metabolic disorders. [ABSTRACT FROM AUTHOR]

Recent development in immunotherapy for cancer treatment has substantiated to be more effective than most of the other treatments. Immunity is the first line of defence of the body; nevertheless, cancerous cells can manipulate immunity compartments to play several roles in tumour progression. Tumour-associated macrophages (TAMs), one of the most dominant components in the tumour microenvironment, are recognized as anti-tumour suppressors. Unfortunately, the complete behaviour of TAMs is still unclear and understudied. TAM density is directly correlated with the progression and poor prognosis of hepatocellular carcinoma (HCC), therefore studying TAMs from different points of view passing by all the factors that may affect its existence, polarization, functions and repolarization are of great importance. Different epigenetic regulations were reported to have a direct relation with both HCC and TAMs. Here, this review discusses different epigenetic regulations that can affect TAMs in HCC whether positively or negatively. [ABSTRACT FROM AUTHOR]

In this study, our objective was to explore the association between gestational diabetes mellitus (GDM) and second trimester maternal plasma levels of lipoxin A4 (LXA4), along with proinflammatory markers such as interleukin-6 (IL-6) and tumour necrosis factor alpha (TNF-α), and the anti-angiogenic factor vascular endothelial growth factor receptor 1 (VEGFR-1) in pregnant women. The study included a cohort of 30 pregnant women with GDM and a control group of 30 normoglycaemic pregnant women matched for age, body mass index, and gestational age. Plasma samples were collected and analysed by enzyme-linked immunosorbent assay to assess specific biomarkers. The GDM group had significantly lower levels of LXA4 and higher levels of TNF-α and VEGFR-1 compared to the control group (p = 0.038, p = 0.025, and p = 0.002, respectively). A statistically significant decrease in the LXA4/TNF-α ratio was observed in the GDM group (p = 0.004). The results suggest that each unit decrease in the LXA4/TNF-α ratio is associated with a 1.280-fold increase in the risk of GDM. These findings suggest a potential diagnostic role for the LXA4/TNFα ratio as a marker for women with GDM. This work provides new insights into the pathogenesis of GDM and highlights the important interplay between inflammation and metabolic dysregulation.

Objective: Rheumatoid arthritis (RA) is a common progressive autoimmune disorder that causes chronic inflammationof the joints and damage to other organs. Previous studies have reported the important role of miRNA-146a in thepathogenesis of RA. In addition, the anti-inflammatory and modulatory effects of oleuropein (OLEU) on the expressionpattern of microRNAs (miRNAs) have been shown in different diseases. Therefore, this study aimed to evaluate boththe sensitivity and specificity of miRNA-146a and determine the potential effects of OLEU on the expression levels ofmiRNA-146a and tumour necrosis factor-alpha (TNF-α) in RA patients.Materials and Methods: The participants in this experimental study were divided into 2 groups: RA (n=45) and healthycontrols (n=30). The isolated peripheral blood mononuclear cells (PBMCs) were treated with different concentrationsof OLEU; and the level of TNF-α expression, anti-citrullinated protein, and miRNA-146a were determined usingenzyme-linked immunoassay and real-time polymerase chain reaction, respectively. In addition, the receiver operatingcharacteristic (ROC) curve analysis evaluated the sensitivity and specificity of miRNA-146a in RA patients.Results: Results revealed a positive correlation between the levels of miRNA-146a expression with the serum levels ofC-reactive protein (CRP) and rheumatoid factor (RF) in RA patients. In addition, OLEU treatment decreased the levelsof TNF-α and miRNA-146a expression in treated PBMCs samples compared with untreated cells. The ROC curveanalysis showed an 85% sensitivity and 100% specificity of miRNA-146a in RA patients.Conclusion: Therefore, miRNA-146a can be used as a useful biomarker for RA diagnosis, particularly for earlydetection. In addition, OLEU could suppress inflammation in RA patients through the regulation of miRNA-146a.

Respiratory tract infections are a common cause of morbidity and mortality globally. The current paper aims to treat this respiratory disorder. Therefore, we elucidated the phytochemical profile of Euphorbia milii flowers and isolated chlorogenic acid (CGA) for the first time. The electrospraying technique was utilized to prepare CGA nanoparticles in polyvinyl alcohol (PVA)/PLGA polymeric matrix. Complete in vitro characterizations were performed to determine particle size, polydispersity index (PDI), zeta potential, loading efficiency (LE), scanning electron microscopy and in vitro release study. The optimum formula (F2) with a particle size (454.36 ± 36.74nm), a surface charge (-4.56 ± 0.84 mV), % of LE (80.23 ± 5.74), an initial burst (29.46 ± 4.79) and % cumulative release (97.42 ± 4.72) were chosen for further activities. In the murine lung infection model, PVA/PLGA NPs loaded with CGA (F2) demonstrated in vivo antibacterial activity against Pseudomonas aeruginosa. Using a plaque assay, the in vitro antiviral activity was investigated. The F2 exhibited antiviral activity against coronavirus (HCoV-229E) and (Middle East respiratory syndrome coronavirus (MERS-CoV), NRCEHKU270). The IC50 of F2 against HCoV-229E and MERS-CoV was 170 ± 1.1 and 223 ± 0.88 μg/mL, respectively. The values of IC50 of F2 were significantly lower (p<.05) than that of free CGA. Therefore, the encapsulation of CGA into electrospray PVA/PLGA NPs would be a promising tool as an antimicrobial agent. [ABSTRACT FROM AUTHOR]

الملخص: أهداف البحث: يرتبط عامل نخر الورم، وهو سيتوكين شحمي، ارتباطا وثيقا باضطراب تحمل الجلوكوز ومقاومة الأنسولين لدى مرضى السكري من النوع الثاني. لم يتم تحديد العلاقة بين تعدد الأشكال في جين عامل نخر الورم ومقاومة الأنسولين لدى المرضى المصابين بالسكري أو مقدمات السكري في بنجلاديش بشكل كامل حتى الآن. تم تصميم الدراسة للكشف عن ارتباط تعدد الأشكال الجيني في جين عامل نخر الورم بمقاومة الأنسولين عند مرضى فرط سكر الدم من أصل بنغلاديشي. طرق البحث: في دراستنا، تم تجنيد 106 شخصا مصابا باضطراب تحمل الجلوكوز، و100مريض سكري من النوع الثاني، و109 من الأشخاص الأصحاء من أصل بنغلاديشي لتحديد تأثير تعدد الأشكال الجيني في جين عامل نخر الورم في الموضع 308 باستخدام التفاعل السلسلي للبوليميريز ثم طريقة تعدد أشكال أطوال الشدف المقتطعة. النتائج: أظهر توزيع تكرار النمط الجيني لعامل نخر الورم -308 ضمن مجموعة التحكم ومجموعة اضطراب تحمل الجلوكوز ومجموعة مرضى السكري النوع الثاني ارتباطًا كبيرا، على الرغم من أن توزيع تكرار الأليل داخل المجموعات أظهر فرقا غير مهم إحصائيا. كما لوحظ أن نقص وظائف خلايا بيتا كان أقل بشكل ملحوظ لدى المرضى ذوي ضرب النمط الجيني. إلى جانب ذلك، تشير نتائجنا إلى أن مؤشر كتلة الجسم وحالة الإقامة للمشاركين في الدراسة كانت مرتبطة بشكل إيجابي مع تعدد الأشكال الجيني. الاستنتاجات: لذلك، يمكن استنتاج أن تعدد الأشكال الجيني في جين عامل نخر الورم في الموضع 308 قد يكون له علاقة سببية بقدرة إفراز الأنسولين المنخفضة وارتفاع مؤشر كتلة الجسم في مجموعات اضطراب تحمل الجلوكوز ومرضى السكري النوع الثاني في بنغلاديش، في حين أن نمط حياة سكان الحضر قد يكون له ارتباط مع تعدد الأشكال الجيني. Abstract: Objectives: Tumour necrosis factor (TNF)-α, an adipocytokine, is closely linked to impaired glucose tolerance (IGT) and insulin resistance (IR) in type 2 diabetes (T2D) subjects. The relationship between the polymorphisms in the TNF-α gene and IR in Bangladeshi prediabetes and T2D subjects has not yet been fully identified. This study aims to reveal the association between TNF-α gene polymorphism and IR in hyperglycaemic patients of Bangladeshi origin. Methods: In our study, 106 IGT, 100 T2D, and 109 healthy subjects of Bangladeshi origin were recruited to identify the impact of TNF-α gene polymorphism at position −308 with a G>A transition using PCR and subsequent restriction fragment length polymorphism (RFLP). Results: The −308G>A TNF-α genotype frequency distribution within the control, IGT, and T2D groups showed a significant association (χ2 = 21.077; P = 0.001), although allele frequency distribution within the groups showed a statistically non-significant difference (χ2 = 1.696; P = 0.091). β-cell functional deficiency (HOMA-B%) was observed to be significantly (P = 0.034) lower in subjects with a variant genotype. In addition, our results indicate that the study subjects’ body mass index (BMI) and residence status were positively correlated (P ≤ 0.05) with −308G>A TNF-α gene polymorphism. Conclusions: Therefore, it can be concluded that −308G>A TNF-α gene polymorphism may have a causative relationship with lower insulin secretory capacity and higher BMI in Bangladeshi IGT and T2D populations, while the urban population's lifestyle might be associated with this polymorphism.

Introduction: Multiple Myeloma (MM) is a clonal expansion of B lineage plasma cells in bone marrow. MM accounts for 10-15% of haematological malignancies and 1% of all malignant diseases. Though, the aetiology of the disease is largely unknown, various factors have been found to increase the incidence of MM. The present comprehensive research work on MM in the Malwa region of central India is an attempt to establish on clinicodemographic, haematological, biochemical and radiological parameters and finally to stage them according to Durie Salmon Staging (DSS) system. Aim: To study clinicopathological profile of patients with MM. Materials and Methods: The present ambispective study was conducted on total 70 cases of MM reported in the Department of Pathology at Sri Aurobindo Medical College and Post Graduate Institute, Indore, Madhya Pradesh, India, from July 2012 to June 2020. The study design included retrospective studies from July 2012 to December 2018 (six years and five months) and prospective studies from November 2017 to April 2019 (one year and five months). The demographic data of patients' including history and clinical findings were recorded. Complete Blood Count (CBC) was done in all cases. Biochemical investigations were also done. Urine samples of all patients were screened for the presence of Bence Jones protein. Biochemical parameters and staging of MM patients was done. Statistical analysis prepared in excels spreadsheet and quantitative data were presented as proportions. Results: The study included a total of 70 cases of MM diagnosed on peripheral smear and/or bone marrow examination. The male:female ratio was 2.1:1, with a male preponderance. The results of the present study, reported 48 (68.57%) patients were male and 22 (31.43%) patients were females. In the present investigation, the authors diagnosed serum Lactate Dehydrogenase (LDH) levels were estimated in 63, out of 70 patients. Out of which, 25 (39.69%) patients had levels <240 U/L, while 23 (33%) and 17 (23.81%) patients had levels between 241-480 U/L and >480 U/L, respectively. Conclusion: The present study, underlines the association between clinical presentation, laboratory parameters and radiological findings in establishing the diagnosis of MM. The present study emphasises not only the role of a bone marrow aspiration and biopsy in establishing a diagnosis of MM, but also, assessing the plasma cell burden in the marrow. [ABSTRACT FROM AUTHOR]

A 28‐year‐old man with ankylosing spondylitis (AS) who was treated with a tumour necrosis factor‐alpha (TNF‐α) inhibitor, adalimumab, presented with newly detected multiple bilateral pulmonary nodules on chest computed tomography (CT). We suspected bacterial infection, including those caused by acid‐fast bacilli, or adalimumab‐related condition, such as sarcoidosis. After adalimumab cessation, no resolution of the pulmonary shadows was observed. Moreover, pulmonary cavitation appeared on chest CT at 7 weeks, prompting surgical lung biopsy. Acid‐fast bacteria culture of the lung tissue showed negative results. Pathological examination suggested that confluent granulomas associated with sarcoidosis might have obstructed the blood vessels, causing necrosis and lung cavitation. Consequently, prednisolone was initiated, and these shadows were reduced. After administering anti‐interleukin (IL)‐17A antibody for treatment of AS and prednisolone withdrawal, these shadows were not exacerbated. TNF‐α inhibitor‐induced sarcoidosis could cause cavitary lesions due to vascular invasion of granulomas. [ABSTRACT FROM AUTHOR]

Available evidence indicates that the various stages of the malaria parasite life cycle elicit specific immune responses of which the relative levels of pro-inflammatory cytokines are key to disease progression, killing the parasite and mediating disease outcomes. This study investigated T-cell response in malaria. Four hundred and sixty-two participants were screened in a community survey of Plasmodium falciparum malaria in Baiyeku, Lagos, Nigeria. P. falciparum parasitaemia was determined by microscopy while the serum levels of IL-10, IFNγ and TNFα were determined by Enzyme-linked immunosorbent assay (ELISA). A total of 70 (15.2 %) participants were microscopically positive for P. falciparum of which 70% were females, 30% were males while children aged 1-17 years were 65.7%. The geometric mean parasite density (GMPD) was significantly (p=0.001) higher among females than males. The GMPD of participants <5 years of age was also significantly (p=0.001) higher than other age groups. About 46.8% of the participants were underweight (Body Mass Index, BMI < 18.5) and also had the highest parasite intensity. The TNFα, IFNγ and IL-10 levels were significantly (p< 0.05) higher in the infected than the uninfected participants. IFN-γ values were significantly (p=0.014) elevated among the symptomatic than the asymptomatic participants while there was no significant difference (P>0.053) in the levels of TNF-α and IL-10 (P>0.093) between the symptomatic and asymptomatic participants. The prevalence of P. falciparum obtained in this study area which is endemic to malaria is 15.2% suggesting a significant reduction of the disease over time due to awareness of the disease in the community. The levels of pro-inflammatory cytokines (IFN-γ and TNF-α) in this study were lower due to the down-regulatory action of the anti-inflammatory cytokines (IL-10). These findings suggest that higher levels of antiinflammatory cytokines, especially IL-10 levels may contribute to the pathogenesis of uncomplicated malaria. [ABSTRACT FROM AUTHOR]

Visceral pain is a leading cause of morbidity in gastrointestinal diseases, which is exacerbated by the gut‐related side‐effects of many analgesics. New treatments are needed and further understanding of the mediators and mechanisms underpinning visceral nociception in disease states is required to facilitate this. The pro‐inflammatory cytokine TNFα is linked to pain in both patients with inflammatory bowel disease and irritable bowel syndrome, and has been shown to sensitize colonic sensory neurons. Somatic, TNFα‐triggered thermal and mechanical hypersensitivity is mediated by TRPV1 signalling and p38 MAPK activity respectively, downstream of TNFR1 receptor activation. We therefore hypothesized that TNFR1‐evoked p38 MAPK activity may also be responsible for TNFα sensitization of colonic afferent responses to the TRPV1 agonist capsaicin, and noxious distension of the bowel. Using Ca2+ imaging of dorsal root ganglion sensory neurons, we observed TNFα‐mediated increases in intracellular [Ca2+] and sensitization of capsaicin responses. The sensitizing effects of TNFα were dependent on TNFR1 expression and attenuated by p38 MAPK inhibition. Consistent with these findings, ex vivo colonic afferent fibre recordings demonstrated an enhanced response to noxious ramp distention of the bowel and bath application of capsaicin following TNFα pre‐treatment. Responses were reversed by p38 MAPK inhibition and absent in tissue from TNFR1 knockout mice. Our findings demonstrate a contribution of TNFR1, p38 MAPK and TRPV1 to TNFα‐induced sensitization of colonic afferents, highlighting the potential utility of these drug targets for the treatment of visceral pain in gastrointestinal disease. Key points: The pro‐inflammatory cytokine TNFα is elevated in gastrointestinal disease and sensitizes colonic afferents via modulation of TRPA1 and NaV1.8 activity. We further develop this understanding by demonstrating a role for p38 MAPK and TRPV1 in TNFα‐mediated colonic afferent sensitization. Specifically, we show that:TNFα sensitizes sensory neurons and colonic afferents to the TRPV1 agonist capsaicin.TNFα‐mediated sensitization of sensory neurons and colonic nociceptors is dependent on TNFR1 expression.TNFα sensitization of sensory neurons and colonic afferents to capsaicin and noxious ramp distension is abolished by inhibition of p38 MAPK.Collectively these data support the utility of targeting TNFα, TNFR1 and their downstream signalling via p38 MAPK for the treatment of visceral pain in gastrointestinal disease. [ABSTRACT FROM AUTHOR]

COVID‐19 has spread globally, affecting almost 160 million individuals. Elderly and pre‐existing patients (such as diabetes, heart disease and asthma) seem more susceptible to severe illness with COVID‐19. Roflumilast was licensed for usage in the European Union in July 2010 as a phosphodiesterase‐4 (PDE4) inhibitor. Under preclinical studies, roflumilast has been shown to decrease bleomycin‐induced lung fibrosis, lung hydroxyproline and right heart thickening. The current study reviewed existing data that the PDE‐4 inhibitor, a roflumilast, protects renal tissues and other major organ systems after COVID‐19 infection by decreasing immune cell infiltration. These immune‐balancing effects of roflumilast were related to a decrease in oxidative and inflammatory burden, caspase‐3 suppression and increased protein kinase A (PKA)/cyclic A.M.P. (cAMP) levels in renal and other organ tissue. [ABSTRACT FROM AUTHOR]

This study aimed to determine the flare rate (FR) in a cohort of Juvenile Idiopathic Arthritis (JIA) patients with tapered or abruptly discontinued biologic disease-modifying anti-rheumatic drugs (bDMARDs) and to identify predictors of flare. This retrospective observational study included 191 bDMARD dose-reduction events in patients with JIA followed-up at a referral hospital during the period 2000–2019. FR was analysed according to reduction strategies. To identify predictors of flare, Kaplan–Meier and Cox-regression models were plotted at 6 months (6 m), 12 months (12 m) and 24 months (24 m) following tapering (TP) or withdrawal (WD). 165 episodes of TP and 71 episodes of WD were included; 45 episodes where treatment was withdrawn after TP were included in both strategies. FR after TP was 13.4% at 6 m and increased up to 26.6% at 12 m and 51.4% at 24 m. After WD, FR was higher, 52.1% of events had a flare at 6 m and 67.6% at 12 m. Previous TP did not increase time in remission after WD of bDMARDs in the Kaplan–Meier analysis. Factors associated with flares were identified after TP at 6 m: female sex, higher number of previous bDMARDs and longer time on bDMARD treatment were positively associated with flares. Polyarticular subtype and younger age at diagnosis were associated with flares at 12 and 24 m after TP. No factors were identified in multivariable analysis after WD. TP is a successful strategy to maintain remission with lower bDMARD doses. Previous TP of bDMARDs does not seem to increase time in remission after WD. [ABSTRACT FROM AUTHOR]

Background: Higher medication anticholinergic burden is associated with increased risk of cardiovascular disease and cognitive decline. A mechanistic pathway has not been established. We aimed to determine whether inflammation may mediate these associations. Methods: Participants were drawn from the European Prospective Investigation into Cancer, Norfolk cohort (40‐79 years at baseline). Anticholinergic burden score (ACB) was calculated at first (1HC) (1993/97) and second (2HC) (1998/2000) health checks. Fibrinogen and C‐reactive protein (CRP) were measured during 1HC and tumour necrosis factor alpha (TNF‐α) and interleukin 6 (IL‐6) during 2HC. Cross‐sectional associations between ACB and inflammatory markers were examined for both health checks. Prospective associations were also examined between 1HC ACB and 2HC inflammatory markers. Models were adjusted for age, sex, lifestyle factors, comorbidities and medications. Results: In total, 17 678 and 22 051 participants were included in cross‐sectional analyses for CRP, and fibrinogen, respectively. Furthermore, 5101 participants with data on TNF‐α and IL‐6 were included in the prospective analyses. Cross‐sectionally, compared to ACB = 0, ACB ≥ 4 was associated with higher fibrinogen, beta (95% confidence interval) = 0.134 g/L (0.070, 0.199), CRP 1.175 mg/L (0.715, 1.634), IL‐6 0.593 pg/mL (0.254, 0.932) and TNF‐α 0.137 pg/mL (0.033, 0.241). In addition, a point increase in ACB was associated with higher levels of all markers. Prospectively, compared to ACB = 0, ACB ≥ 4 was associated with higher IL‐6(pg/mL) of 0.019 (−0.323, 0.361) and TNF‐α (pg/mL) of 0.202% (0.81, 0.323). A unit increase in ACB was associated with a significantly higher TNF‐α and IL‐6. Conclusion: Higher ACB was associated with higher inflammatory markers. Inflammation may mediate the relationship between anticholinergic medications and adverse outcomes. [ABSTRACT FROM AUTHOR]

Abstract Background Inflammation and oxidative stress can contribute to the development and progression of heart failure. This study aimed to investigate the association between inflammatory and oxidative stress markers in dogs with congestive heart failure (CHF). Associations between the disease severity marker N-terminal pro-B-type natriuretic peptide (NT-proBNP) and markers of inflammation and oxidative stress were also determined. Results Thirty-seven dogs with cardiovascular diseases (dilated cardiomyopathy, DCM (16 dogs), myxomatous mitral valve disease, MMVD (21 dogs)) and ten healthy dogs were included in this prospective study. The patients were further divided into groups with (26) and without CHF (11). We found a significantly higher serum concentration of C-reactive protein (P = 0.012), white blood cell (P = 0.001), neutrophil (P = 0.001) and monocyte counts (P = 0.001) in patients with CHF compared to control dogs. The concentration of tumor necrosis factor-alpha (TNF-α) was significantly higher in patients with CHF compared to patients without CHF (P = 0.030). No significant difference was found in most of the measured parameters between MMVD and DCM patients, except for glutathione peroxidase (GPX) and NT-proBNP. In patients with CHF, TNF-α correlated positively with malondialdehyde (P = 0.014, r = 0.474) and negatively with GPX (P = 0.026, r = − 0.453), and interleukin-6 correlated negatively with GPX (P = 0.046, r = − 0.412). NT-proBNP correlated positively with malondialdehyde (P = 0.011, r = 0.493). In patients without CHF none of the inflammatory and oxidative stress markers correlated significantly. Furthermore, in the group of all cardiac patients, GPX activity significantly negatively correlated with NT-proBNP (P = 0.050, r = − 0.339) and several markers of inflammation, including TNF-α (P = 0.010, r = − 0.436), interleukin-6 (P = 0.026, r = − 0.382), white blood cell (P = 0.032, r = − 0.369), neutrophil (P = 0.027, r = − 0.379) and monocyte counts (P = 0.024, r = − 0.386). Conclusion Inflammatory and oxidative stress markers are linked in canine CHF patients, but not in patients without CHF. These results suggest complex cross communication between the two biological pathways in advanced stages of CHF.

Abstract Background The innate immune response against various life cycle stages of the malaria parasite plays an important role in protection against the disease and regulation of its severity. Phagocytosis of asexual erythrocytic stages is well documented, but little and contrasting results are available about phagocytic clearance of sexual stages, the gametocytes, which are responsible for the transmission of the parasites from humans to mosquitoes. Similarly, activation of host macrophages by gametocytes has not yet been carefully addressed. Methods Phagocytosis of early or late Plasmodium falciparum gametocytes was evaluated through methanol fixed cytospin preparations of immortalized mouse C57Bl/6 bone marrow-derived macrophages treated for 2 h with P. falciparum and stained with Giemsa, and it was confirmed through a standardized bioluminescent method using the transgenic P. falciparum 3D7elo1-pfs16-CBG99 strain. Activation was evaluated by measuring nitric oxide or cytokine levels in the supernatants of immortalized mouse C57Bl/6 bone marrow-derived macrophages treated with early or late gametocytes. Results The results showed that murine bone marrow-derived macrophages can phagocytose both early and late gametocytes, but only the latter were able to induce the production of inflammatory mediators, specifically nitric oxide and the cytokines tumour necrosis factor and macrophage inflammatory protein 2. Conclusions These results support the hypothesis that developing gametocytes interact in different ways with innate immune cells of the host. Moreover, the present study proposes that early and late gametocytes act differently as targets for innate immune responses.

Context Gynura procumbens (Lour.) Merr. (Asteraceae) has been reported to have various pharmacological activities including anti-inflammatory effects. Objective This study sought to determine whether Gynura procumbens (GP) could improve vascular reactivity by suppressing inflammation in postmenopausal rats fed with five-times heated palm oil (5HPO) diet. Materials and methods Forty-eight female Sprague-Dawley rats were randomly divided into sham [non-ovariectomized; grouped as control, GP extracts (250 and 500 mg/kg), atorvastatin (ATV, 10 mg/kg)] and postmenopausal (PM) groups [ovariectomized rats fed with 5HPO; grouped as PM, GP extracts (250 and 500 mg/kg) and ATV (10 mg/kg)]. Each group (n = 6) was either supplemented with GP extract or ATV orally once daily for 6 months. Results In comparison with the untreated PM group, 250 and 500 mg/kg GP supplementation to PM groups reduced the systolic blood pressure (103 ± 2.7, 86 ± 2.4 vs. 156 ± 7.83 mmHg, p

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The post‐menopausal stage in women's life is associated with the enhancement of inflammation that may be reduced using soy isoflavones or soy protein. The present study aimed to summarize the effect of soy isoflavones plus soy protein on circulating interleukin‐6 (IL‐6) and tumour necrosis factor‐α (TNF‐α) in post‐menopausal women. The English‐language articles were identified from the databases such as Cochrane Library, clinicaltrials.gov, Web of Science, PubMed, and Scopus until December 2020. The mean change from baseline and its standard deviation (SD) for intervention and comparison groups were used to calculate the effect size. The statistical heterogeneity of the intervention effects was computing by Cochran's Q test and I2 statistic. Nine and seven studies were selected for systematic review and meta‐analysis, respectively. The results of our meta‐analysis indicated a non‐significant effect on the serum concentrations of IL‐6 and TNF‐α (weighted mean differences [WMD] = 0.07 pg/mL; 95% confidence interval [CI] = −0.03, 0.17 pg/mL; P = 0.190; WMD =0.05 pg/mL; 95% CI = −0.01, 0.12 pg/mL; P = 0.092; respectively). In subgroup analysis, soy isoflavones plus soy protein could increase the serum concentration of IL‐6 in studies with soy isoflavones dose ≤87 mg/days, cross‐over design, weak quality, and studies on participants who had health risk factors or diseases. The serum concentration of TNF‐α increased in studies with cross‐over design, intervention duration ≤56 days, and body mass index (BMI) >27, and in studies that were conducted on at‐risk or sick participants. In conclusion, our meta‐analysis did not confirm any significant effect on serum concentration of IL‐6 and TNF‐α among post‐menopausal women. [ABSTRACT FROM AUTHOR]

Objective: Unipolar mania is not included in the diagnostic and statistical manual of mental disorders-5 (DSM-5) as a separate diagnosis, although it is defined by widely accepted diagnostic criteria. The aim of this study was to investigate the differences between unipolar mania and bipolar disorder in terms of clinical and inflammatory parameters. Methods: The data of 495 hospitalised patients with bipolar disorder diagnoses were analysed retrospectively. Forty met the diagnostic criteria for unipolar mania. Two patients refused to participate in the study. Thirty-eight unipolar mania patients and 42 randomly selected patients with bipolar disorder diagnosis were included in the study. The two groups were compared in terms of sociodemographic, clinical characteristics, serum brain-derived neurotrophic factor, C-reactive protein (CRP), leucocyte and cytokine levels. Results: A total of 40 (8.08%) of 495 patients diagnosed with bipolar disorder met the unipolar mania diagnostic criteria. The number of manic episodes and the number of hospitalisations were statistically higher in the unipolar mania group than in the bipolar disorder group. Among all the manic symptoms, the incidence of symptoms such as euphoria, increased sexual interest, grandiosity and delusions were found to be statistically higher in the unipolar mania group. Interleukin (IL)-6 and CRP levels were significantly higher in the unipolar mania group than in the bipolar disorder group. Conclusion: Unipolar mania differs from bipolar disorder in terms of clinical features and serum IL-6 and CRP levels. [ABSTRACT FROM AUTHOR]

Gynura procumbens (Lour.) Merr. (Asteraceae) has been reported to have various pharmacological activities including anti-inflammatory effects. This study sought to determine whether Gynura procumbens (GP) could improve vascular reactivity by suppressing inflammation in postmenopausal rats fed with five-times heated palm oil (5HPO) diet. Forty-eight female Sprague-Dawley rats were randomly divided into sham [non-ovariectomized; grouped as control, GP extracts (250 and 500 mg/kg), atorvastatin (ATV, 10 mg/kg)] and postmenopausal (PM) groups [ovariectomized rats fed with 5HPO; grouped as PM, GP extracts (250 and 500 mg/kg) and ATV (10 mg/kg)]. Each group (n = 6) was either supplemented with GP extract or ATV orally once daily for 6 months. In comparison with the untreated PM group, 250 and 500 mg/kg GP supplementation to PM groups reduced the systolic blood pressure (103 ± 2.7, 86 ± 2.4 vs. 156 ± 7.83 mmHg, p < 0.05), intima-media thickness (101.28 ± 3.4, 93.91 ± 2.93 vs. 143.78 ± 3.31 µM), vasoconstriction percentage induced by phenylephrine (102.5%, 88.3%, vs. 51.8%), sICAM-1 (0.49, 0.26 vs. 0.56 pg/mL) and sVCAM-1 (0.39, 0.25 vs. 0.45 pg/mL). GP extract supplementation increased vasorelaxation percentage induced by acetylcholine (78.4% vs. 47.3%) and sodium nitroprusside (84.2% vs. 53.7%), increased changes in plasma nitric oxide level (1.25%, 1.31% vs. 1.9%), and suppressed the elevation of TNF-α (0.39 vs. 1.02 pg/mL), IL-6 (0.43 vs. 0.77 pg/mL) and CRP (0.29 vs. 0.69 ng/mL) in the PM groups. GP extract might improve vascular dysfunction by suppressing the inflammatory response, consequently preventing blood pressure elevation. [ABSTRACT FROM AUTHOR]

Abstract Background Symptoms and comorbidities of ankylosing spondylitis (AS) considerably reduce health-related quality of life (HRQoL) and ability to work. This real-world study assessed rates of tumour necrosis factor inhibitor (TNFi) use and switching, treatment failure, and associations between failing TNFi and HRQoL, work productivity and activity impairment (WPAI). Methods AS patients and their treating physicians completed questionnaires capturing patient demographics, clinical status, TNFi treatment history, reasons for switching TNFi, HRQoL and WPAI. Current TNFi was determined as “failing” if, after ≥3 months, physician-rated disease severity had worsened, remained severe, was “unstable/deteriorating”, physicians were dissatisfied with disease control and/or did not consider treatment a “success”. Results The analysis included 2866 AS patients from 18 countries. Of 2795 patients with complete treatment data, 916 (32.8%) patients had never received TNFi therapy, 1623 (58.1%) patients were receiving their 1st TNFi and 200 (7.2%) patients had ever received ≥2 TNFi (treatment switch). Primary or secondary lack of efficacy were the commonest reasons for switching, and the mean delay in switching after primary lack of efficacy was 11.1 months. 232 (15.4%) patients on TNFi were currently “failing” who, compared to those with treatment success, reported poorer HRQoL: 5-dimension EuroQoL (EQ-5D-3 L): 0.63 vs. 0.78; Medical Outcomes Study Short-Form Health Survey version 2 (SF-36v2) mental component summary (MCS): 41.8 vs. 46.3; physical component summary (PCS): 40.2 vs. 45.1; impaired work productivity: 46.4% vs. 25.0%; and activity: 44.5% vs. 29.6%; all P

Macrophage activation syndrome (MAS) is a form of secondary hemophagocytic lymphohistiocytosis and is a rapidly progressive, life-threatening complication of adult-onset Still's disease (AOSD). An anti-IL-6 receptor monoclonal antibody, tocilizumab, has shown to be effective in the treatment of AOSD but may precipitate MAS in patients with AOSD. The precise mechanism of MAS developed during anti-cytokine biologic agents remains unknown, but selective inhibition of a subset of pathways could impact other immune signalling pathways and trigger MAS. We herein describe a case of AOSD with the opposite outcomes of tocilizumab therapy, remission and development of MAS, after tocilizumab treatment at the initial flare and the relapse. From the comparison of clinical characteristics and concomitant treatment around the time of starting tocilizumab in both flares, the type and intensity of concomitant immunosuppressive therapy might strongly affect MAS development during tocilizumab therapy. [ABSTRACT FROM AUTHOR]

Background: Inflammation and oxidative stress can contribute to the development and progression of heart failure. This study aimed to investigate the association between inflammatory and oxidative stress markers in dogs with congestive heart failure (CHF). Associations between the disease severity marker N-terminal pro-B-type natriuretic peptide (NT-proBNP) and markers of inflammation and oxidative stress were also determined. Results: Thirty-seven dogs with cardiovascular diseases (dilated cardiomyopathy, DCM (16 dogs), myxomatous mitral valve disease, MMVD (21 dogs)) and ten healthy dogs were included in this prospective study. The patients were further divided into groups with (26) and without CHF (11). We found a significantly higher serum concentration of C-reactive protein (P = 0.012), white blood cell (P = 0.001), neutrophil (P = 0.001) and monocyte counts (P = 0.001) in patients with CHF compared to control dogs. The concentration of tumor necrosis factor-alpha (TNF-α) was significantly higher in patients with CHF compared to patients without CHF (P = 0.030). No significant difference was found in most of the measured parameters between MMVD and DCM patients, except for glutathione peroxidase (GPX) and NT-proBNP. In patients with CHF, TNF-α correlated positively with malondialdehyde (P = 0.014, r = 0.474) and negatively with GPX (P = 0.026, r = − 0.453), and interleukin-6 correlated negatively with GPX (P = 0.046, r = − 0.412). NT-proBNP correlated positively with malondialdehyde (P = 0.011, r = 0.493). In patients without CHF none of the inflammatory and oxidative stress markers correlated significantly. Furthermore, in the group of all cardiac patients, GPX activity significantly negatively correlated with NT-proBNP (P = 0.050, r = − 0.339) and several markers of inflammation, including TNF-α (P = 0.010, r = − 0.436), interleukin-6 (P = 0.026, r = − 0.382), white blood cell (P = 0.032, r = − 0.369), neutrophil (P = 0.027, r = − 0.379) and monocyte counts (P = 0.024, r = − 0.386). Conclusion: Inflammatory and oxidative stress markers are linked in canine CHF patients, but not in patients without CHF. These results suggest complex cross communication between the two biological pathways in advanced stages of CHF. [ABSTRACT FROM AUTHOR]

Background: The aim of this study was to investigate the anti-inflammatory and antioxidant effects of Coriandrum sativum extract on liver ischaemia reperfusion injury at light microscopic and biochemical levels.Materials and Methods: Sham, ischaemia/reperfusion injury (IRI), IRI + Coriandrum sativum extract and only Coriandrum sativum extract groups were formed. Sixty minutes of ischaemia and 60 minutes of reperfusion were performed. In the treatment group, 300 mg/kg/day Coriandrum sativum was given by gavage. Hepatic tissues were fixed in 4% paraformaldehyde. Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP) enzymes were measured. Nuclear factor-kappa beta (NF-κB), tumour necrosis factor-alpha (TNF-α) and caspase-3 immunohistochemistry staining was performed. Microscopic scoring was performed in terms of sinusoidal congestion, vacuolisation, and necrosis.Results: Sinusoidal enlargement and diffuse congestion, Kupffer cell increase, neutrophil increase in necrotic areas, vacuolisation in hepatocytes, and bile duct proliferation in the portal triad were observed in ischaemia/reperfusion hepatic tissue. Very rare, necrotic areas were observed in the Coriandrum sativum treatment group, while congestion and vacuolisation and bile duct proliferation were decreased compared to the ischaemic group. The AST and ALT levels were increased in the IRI and IRI + Coriandrum sativum groups. When compared to the IRI group, the AST and ALT levels of the Coriandrum sativum were considerably decreased. The IRI and IRI + Coriandrum sativum groups had statistically significant differences in ALP compared to that of the Coriandrum sativum and Sham groups. There was no significant difference between the ALP levels of the IRI and IRI + Coriandrum sativum groups TNF-α, NF-κB and caspase-3 immune positive stained hepatocytes were numerous and widely observed in the injury group. There were positive TNF-α immunohistochemical staining Kupffer cells in the IRI group. In the group treated with Coriandrum sativum, Kupffer cells were not stained, while TNF-α, NF κB and caspase-3 expressing hepatocytes were found to be decreased compared to the IRI group. When the expression values of the TNF-α, NF-κB and caspase-3 groups were evaluated statistically, it was seen that there was a significant decrease in the group treated with Coriandrum sativum.Conclusions: It was found that Coriandrum sativum extract decreased proinflammatory cytokine TNF-α and apoptotic cell death and liver enzymes in liver ischaemia/reperfusion injury. [ABSTRACT FROM AUTHOR]

Background: Rheumatoid arthritis is a chronic autoimmune disease that primarily causes inflammation, pain and stiffness in the joints. People with severe disease may be treated with biological disease-modifying anti-rheumatic drugs, including tumour necrosis factor-α inhibitors, but the efficacy of these drugs is hampered by the presence of anti-drug antibodies. Monitoring the response to these treatments typically involves clinical assessment using response criteria, such as Disease Activity Score in 28 joints or European League Against Rheumatism. Enzyme-linked immunosorbent assays can also be used to measure drug and antibody levels in the blood. These tests may inform whether or not adjustments to treatment are required or help clinicians to understand the reasons for treatment non-response or a loss of response. Methods: Systematic reviews were conducted to identify studies reporting on the clinical effectiveness and cost-effectiveness of using enzyme-linked immunosorbent assays to measure drug and anti-drug antibody levels to monitor the response to tumour necrosis factor-α inhibitors [adalimumab (Humira®; AbbVie, Inc., North Chicago, IL, USA), etanercept (Enbrel®; Pfizer, Inc., New York, NY, USA), infliximab (Remicade®, Merck Sharp & Dohme Limited, Hoddesdon, UK), certolizumab pegol (Cimzia®; UCB Pharma Limited, Slough, UK) and golimumab (Simponi®; Merck Sharp & Dohme Limited)] in people with rheumatoid arthritis who had either achieved treatment target (remission or low disease activity) or shown primary or secondary non-response to treatment. A range of bibliographic databases, including MEDLINE, EMBASE and CENTRAL (Cochrane Central Register of Controlled Trials), were searched from inception to November 2018. The risk of bias was assessed using the Cochrane ROBINS-1 (Risk Of Bias In Non-randomised Studies – of Interventions) tool for non-randomised studies, with adaptations as appropriate. Threshold and cost–utility analyses that were based on a decision tree model were conducted to estimate the economic outcomes of adding therapeutic drug monitoring to standard care. The costs and resource use were considered from the perspective of the NHS and Personal Social Services. No discounting was applied to the costs and effects owing to the short-term time horizon of 18 months that was adopted in the economic analysis. The impact on the results of variations in testing and treatment strategies was explored in numerous clinically plausible sensitivity analyses. Results: Two studies were identified: (1) a non-randomised controlled trial, INGEBIO, that compared standard care with therapeutic drug monitoring using Promonitor® assays [Progenika Biopharma SA (a Grifols–Progenika company), Derio, Spain] in Spanish patients receiving adalimumab who had achieved remission or low disease activity; and (2) a historical control study. The economic analyses were informed by INGEBIO. Different outcomes from INGEBIO produced inconsistent results in both threshold and cost–utility analyses. The cost-effectiveness of therapeutic drug monitoring varied, from the intervention being dominant to the incremental cost-effectiveness ratio of £164,009 per quality-adjusted life-year gained. However, when the frequency of testing was assumed to be once per year and the cost of phlebotomy appointments was excluded, therapeutic drug monitoring dominated standard care. Limitations: There is limited relevant research evidence and much uncertainty about the clinical effectiveness and cost-effectiveness of using enzyme-linked immunosorbent assay-based testing for therapeutic drug monitoring in rheumatoid arthritis patients. INGEBIO had serious limitations in relation to the National Institute for Health and Care Excellence scope: only one-third of participants had rheumatoid arthritis, the analyses were mostly not by intention to treat and the follow-up was 18 months only. Moreover, the outcomes might not be generalisable to the NHS. Conclusions: Based on the available evidence, no firm conclusions could be made about the cost-effectiveness of therapeutic drug monitoring in England and Wales. Future work: Further controlled trials are required to assess the impact of using enzyme-linked immunosorbent assays for monitoring the anti-tumour necrosis factors in people with rheumatoid arthritis. Study registration: This study is registered as PROSPERO CRD42018105195. Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 8. See the NIHR Journals Library website for further project information.

Purpose Present study was undertaken to evaluate and compare the salivary levels of tumour necrosis factor alpha (TNF-α) in subjects with RAS, traumatic ulcers (TUs) in the oral mucosa and in healthy controls. Materials and Methods Present study involved 90 participants of which 30 subjects were diagnosed with RAS, 30 subjects with TUs and 30 healthy controls grouped as group 1, group 2 and group 3 respectively. Unstimulated saliva was collected from the subjects through ‘Spit Technique’ and the estimation of TNF-α was done by enzyme linked immunosorbent assay. The data collected was statistically analysed. Results Salivary level of TNF-α was significantly higher in RAS patients than in patients with TUs and healthy controls. Difference between the Salivary TNF-α level in our study groups were statistically significant (p

DOI: 10.26650/eor.2018.543Purpose Present study was undertaken to evaluate and compare the salivary levels of tumour necrosis factor alpha (TNF-α) in subjects with RAS, traumatic ulcers (TUs) in the oral mucosa and in healthy controls. Materials and Methods Present study involved 90 participants of which 30 subjects were diagnosed with RAS, 30 subjects with TUs and 30 healthy controls grouped as group 1, group 2 and group 3 respectively. Unstimulated saliva was collected from the subjects through ‘Spit Technique’ and the estimation of TNF-α was done by enzyme linked immunosorbent assay. The data collected was statistically analysed. Results Salivary level of TNF-α was significantly higher in RAS patients than in patients with TUs and healthy controls. Difference between the Salivary TNF-α level in our study groups were statistically significant (p

Abstract Background Adult mesenchymal stem cells (MSCs) play a crucial role in the maintenance of tissue homeostasis and in regenerative processes. Among the different MSC types, the gingiva-derived mesenchymal stem cells (GMSCs) have arisen as a promising tool to promote the repair of damaged tissues secreting trophic mediators that affect different types of cells involved in regenerative processes. Tumour necrosis factor (TNF)-α is one of the key mediators of inflammation that could affect tissue regenerative processes and modify the MSC properties in in-vitro applications. To date, no data have been reported on the effects of TNF-α on GMSC trophic activities and how its modulation with anti-inflammatory agents from natural sources could modulate the GMSC properties. Methods GMSCs were isolated and characterized from healthy subjects. The effects of TNF-α were evaluated on GMSCs and on the well-being of endothelial cells. The secretion of cytokines was measured and related to the modification of GMSC-endothelial cell communication using a conditioned-medium method. The ability to modify the inflammatory response was evaluated in the presence of Ribes nigrum bud extract (RBE). Results TNF-α differently affected GMSC proliferation and the expression of inflammatory-related proteins (interleukin (IL)-6, IL-10, transforming growth factor (TGF)-β, and cyclooxygenase (COX)-2) dependent on its concentration. A high TNF-α concentration decreased the GMSC viability and impaired the positive cross-talk between GMSCs and endothelial cells, probably by enhancing the amount of pro-inflammatory cytokines in the GMSC secretome. RBE restored the beneficial effects of GMSCs on endothelial viability and motility under inflammatory conditions. Conclusions A high TNF-α concentration decreased the well-being of GMSCs, modifying their trophic activities and decreasing endothelial cell healing. These data highlight the importance of controlling TNF-α concentrations to maintain the trophic activity of GMSCs. Furthermore, the use of natural anti-inflammatory agents restored the regenerative properties of GMSCs on endothelial cells, opening the way to the use and development of natural extracts in wound healing, periodontal regeneration, and tissue-engineering applications that use MSCs.

Background: The innate immune response against various life cycle stages of the malaria parasite plays an important role in protection against the disease and regulation of its severity. Phagocytosis of asexual erythrocytic stages is well documented, but little and contrasting results are available about phagocytic clearance of sexual stages, the gametocytes, which are responsible for the transmission of the parasites from humans to mosquitoes. Similarly, activation of host macrophages by gametocytes has not yet been carefully addressed. Methods: Phagocytosis of early or late Plasmodium falciparum gametocytes was evaluated through methanol fixed cytospin preparations of immortalized mouse C57Bl/6 bone marrow-derived macrophages treated for 2 h with P. falciparum and stained with Giemsa, and it was confirmed through a standardized bioluminescent method using the transgenic P. falciparum 3D7elo1-pfs16-CBG99 strain. Activation was evaluated by measuring nitric oxide or cytokine levels in the supernatants of immortalized mouse C57Bl/6 bone marrow-derived macrophages treated with early or late gametocytes. Results: The results showed that murine bone marrow-derived macrophages can phagocytose both early and late gametocytes, but only the latter were able to induce the production of inflammatory mediators, specifically nitric oxide and the cytokines tumour necrosis factor and macrophage inflammatory protein 2. Conclusions: These results support the hypothesis that developing gametocytes interact in different ways with innate immune cells of the host. Moreover, the present study proposes that early and late gametocytes act differently as targets for innate immune responses. [ABSTRACT FROM AUTHOR]

A feeding trial was conducted to explore the effect of dietary Houttuynia cordata leaf extract (HCLE) and leaf meal (HCLM) on immunological responses and expression of interferon‐gamma (IFN‐γ) and tumour necrosis factor‐alpha (TNF‐α) gene in Labeo rohita fingerlings. Six isonitrogenous (350 g/kg CP) and isocaloric (17 MJ/kg DE) purified experimental diets were formulated with Houttuynia cordata leaf extract and leaf meal comprising control, C (0 g/kg HCLE and HCLM), E2.5 (2.5 g/kg HCLE), E5 (5 g/kg HCLE), E10 (10 g/kg HCLE), M10 (10 g/kg HCLM) and M20 (20 g/kg HCLM). Labeo rohita fingerlings (3.37 ± 0.23 g) were distributed in six experimental groups in triplicates following the complete random distribution. Fish were fed twice daily with respective experimental diets for a period of 60 days. A significantly (p <.05) lower lactate dehydrogenase, malate dehydrogenase, superoxide dismutase and catalase activities were registered in supplemented groups compared with control group, while respiratory burst and lysozyme activities were significantly (p <.05) higher in E10 group compared with other experimental groups. Haemoglobin, total leucocyte count, total erythrocyte count and haematocrit values were significantly (p <.05) higher in E10 group. The expression of IFN‐γ and TNF‐α in both the kidney and liver was significantly up‐regulated in leaf extract and meal supplemented groups with the highest expression in the fish of E10 group. Overall, these results suggest that the dietary supplementation of ethanolic extract of the Houttuynia cordata leaf at 10 g/kg level can enhance the immune response of L. rohita fingerlings. [ABSTRACT FROM AUTHOR]

Background: Synovial cysts are currently classified as degenerative lesions affecting the joint capsule or adjacent structures.Materials and Methods: In our study we describe the results obtained in an immunohistochemical study comprising 18 patients with synovial cysts, performed to evaluate the pathophysiological role of some inflammatory cytokines such as: interleukin (IL)-1β, IL-6 and tumour necrosis factor-alpha (TNF-α).Results: Results showed an over-expression of TNF-α, IL-1β and IL-6 which appears to be involved in the onset and progression of the disease. At the present time it is not possible to affirm that these molecules play a direct role also due to the absence of further and more specific investigations. The authors therefore hypothesize that inhibition of inflammation may have a significant role in the pathogenesis and regression of synovial cysts.Conclusions: Hence, these inflammatory cytokines may be considered potential therapeutic targets. The development of synthetic inhibitors of these inflammatory factors could lead to a reduction in the intensity of inflammation, thus inhibiting the onset and development of the disease. [ABSTRACT FROM AUTHOR]

Although some serum biomarkers are elevated in both Kawasaki disease (KD) and infections, these conditions have not been compared by individual or combined biomarkers. The aim of this study, undertaken between January 2016 and May 2018 in a large teaching hospital, was to compare the serum concentration of cytokines, metalloproteinases (MMP) and heat shock protein (HSP) between cases defined as children with Kawasaki disease (KD) and those with febrile infections (controls). Serum concentrations of tumour necrosis factor-alpha (TNF-alpha), interleukins (IL 1beta, 6, and 8), heat shock proteins (HSP 60 and 70) and matrix metalloproteinase (MMP 9) were measured on admission in 17 children under six years of age with a temperature >38.5 °C for ≥five days, and compared between the two groups. The median age was 25 months and the median duration of fever eight days. Seven children were diagnosed with KD and ten had a febrile infection. Only the serum concentrations of IL-6 and TNF-alpha were significantly higher in the former than in the latter group (P = 0.01 and 0.04 respectively). To differentiate between the two groups with the best sensitivity and specificity, the optimal cut-off value for IL-6 was 12.6 pg/mL, and for TNF-alpha 47.9 pg/mL. Their combined increase, however, outperformed their individual concentrations. The characteristic diagnostic "signature" of the combined elevation of IL-6 and TNF-alpha serum levels has the potential, in febrile children, to differentiate early KD from febrile infections, allowing the institution of appropriate therapy. [ABSTRACT FROM AUTHOR]

Aim: To investigate the possible association between TNFα (−308 G/A) and IL‐1β (−511 C/T) single nucleotide polymorphisms (SNPs) and GSTT and GSTM deletion polymorphisms and risk of apical periodontitis (AP) development, and determine the association of different genotypes with the presence of herpesviral infection in AP. Methodology: The study included 120 periapical lesions and 200 control samples. Gene polymorphism analysis was performed using either polymerase chain reaction (PCR) or PCR/ restriction fragment length polymorphism (RFLP). Relative gene expression of TNF‐α and IL‐1β was analysed using reverse transcriptase – real‐time PCR. The presence of Epstein–Barr virus (EBV) and human cytomegalovirus (HCMV) was assessed by nested PCR. Chi‐square and Fisher's exact tests and logistic regression analyses were done for polymorphisms, whilst Mann–Whitney U‐test was performed for the expression analysis. The expected frequency of variants was analysed by the Hardy–Weinberg equilibrium test. Results: TNF‐α (−308 G/A) SNP increased AP susceptibility for heterozygous (odds ratio (OR) = 1.72, 95% confidence interval (CI) = 1.06–2.80, P = 0.027) and homozygous (OR = 8.55, 95% CI = 1.77–41.36, P < 0.001) carriers of the variant A allele. On the other hand, IL‐1β (−511 C/T) polymorphism exerted a protective effect both in heterozygotes (OR = 0.540, 95% CI = 0.332–0.880, P = 0.013) and homozygotes (OR = 0.114, 95% CI = 0.026–0.501, P < 0.001). In addition, GSTM1 and GSTT1 null genotypes separately, as well as concomitantly, were associated with an increased risk for AP development (P < 0.001). The null GSTT1 genotype increased approximately twice the risk of Epstein–Barr infection (EBV) in AP (OR = 2.17, 95% CI = 1–4.71, P = 0.048), whilst TNF‐α SNP decreased it, both in heterozygotes (OR = 0.20, 95% CI = 0.08–0.48, P < 0.001) and AA homozygotes (OR = 0.07, 95% CI = 0.01–0.37, P = 0.001). Conclusions: GSTM and GSTT deletion polymorphisms, as well as TNFα (−308 G/A) SNP, are associated with increased risk, whereas IL‐1β (−511 C/T) polymorphism decreases the risk of AP development. GSTT and TNFα polymorphisms also appear to modulate the risk of EBV infection in Serbian patients with AP. [ABSTRACT FROM AUTHOR]

Alpha‐pinene (α‐pinene) is an organic compound, found in the oils of many species of coniferous trees, especially pine. α‐Pinene reportedly has antioxidant and anti‐inflammatory activities; however, its effects on osteoblasts are unknown. This study investigated the effects of α‐pinene on osteoblast differentiation and tumour necrosis factor‐alpha (TNFα)‐induced inhibition of osteogenesis. Culture in control or osteogenic medium containing α‐pinene increased osteogenic marker expression. Alkaline phosphatase staining and alizarin red S staining confirmed that α‐pinene enhanced osteoblast differentiation. Also, α‐pinene attenuated TNFα‐induced inhibition of Smad1/5/9 phosphorylation and extracellular matrix mineralization. Taken together, our findings suggest that α‐pinene enhances osteoblast differentiation and mineralization in MC3T3‐E1 pre‐osteoblasts. [ABSTRACT FROM AUTHOR]

The therapeutic potential of the antimicrobial peptide cathelicidin (Camp) administration in sepsis has been widely investigated. However, little is known about the pathophysiological roles of cathelicidin in septic cardiomyopathy. In a lipopolysaccharide (LPS)‐induced endotoxaemic model, we found that the mRNA and protein expression of cardiac cathelicidin were induced in C57BL/6J wild‐type (WT) mice upon LPS challenge, accompanied by increased circulating cathelicidin levels. We showed that this peptide was mainly derived from neutrophils and monocytes/macrophages. Camp deficiency exacerbated LPS‐induced myocardial depression, while the administration of CRAMP (the mature form of mouse cathelicidin) decreased the LPS‐induced mortality in a D‐galactosamine hydrochloride (D‐GalN)‐sensitized endotoxin shock model. In vivo, LPS‐treated Camp knockout mice had a significant higher protein level of myocardial and circulating tumour necrosis factor‐alpha (TNF‐α), a major contributing factor to septic cardiomyopathy, compared to LPS‐treated WT mice, while CRAMP administration inhibited LPS‐induced TNF‐α production in the heart and plasma in D‐GalN‐sensitized endotoxaemic mice. In vitro, CRAMP treatment suppressed LPS‐induced Tnf‐α mRNA expression in cultured neonatal mouse cardiomyocytes and reduced TNF‐α secretion in the culture supernatant. The inhibitory effects of CRAMP on TNF‐α production may be related to its neutralizing ability of LPS, since CRAMP application had no effects on another toll‐like receptor 4 ligand paclitaxel‐induced Tnf‐α mRNA expression in cardiomyocytes. These findings suggest that LPS‐induced cathelicidin protects the heart against myocardial depression partly through the inhibition of TNF‐α production via neutralizing LPS. [ABSTRACT FROM AUTHOR]