Pharmacological basis for use of madecassoside in gouty arthritis: anti-inflammatory,anti-hyperuricemic,and NLRP3 inhibition

Objectives: Gouty arthritis is caused by the deposition of monosodium urate (MSU) crystals in joints, which is associated with the rise of serum urate content. This study aims to investigate the therapeutic effect of Madecassoside on gouty arthritis and hyperuricemia.

Methods: DBA/1 mice were intradermally injected with MSU to stimulate joint inflammation or intraperitoneally injected with MSU to trigger peritonitis. Moreover, ICR mice were exposed to potassium oxonate to stimulate hyperuricemia.

Results: Madecassoside repressed MSU-triggered pad swelling, joint 99mTc uptake, and joint inflammation in DBA/1 mice with gouty arthritis. Neutrophil infiltration and IL-1β & IL-6 & MCP-1 secretion was also alleviated in lavage fluids from DBA/1 mice with peritonitis due to Madecassoside treatment. Furthermore, Madecassoside decreased MSU-induced neutrophil cytosolic factor 1, caspase-1 and NLRP3 expression in mice with peritoneal inflammation. In hyperuricemic mice, Madecassoside improved renal dysfunction. Serum uric acid, BUN, and creatinine were down-regulated by Madecassoside.

Conclusion: These findings indicate that Madecassoside has potential to ameliorate inflammation in both acute gouty arthritis model and peritonitis model, probably via regulating IL-1β and NLRP3 expression.

Practical point: Madecassoside also exhibited a urate-lowering effect and a renal protective effect in hyperuricemic mice.     

Tachykinin upregulation in atopic dermatitis

Context: Atopic dermatitis (AD) is a chronic, inflammatory, itching skin disorder, which may worsen due to stress, depression and anxiety. Tachykinins may be involved in inflammation signaling as well as they may have a role in stress, depression and anxiety.

Objective: This study aimed to measure the expression of tachykinin markers, in the skin of patients with AD, and the correlation of these tachykinins with clinical and psychodemographic parameters.

Materials and methods: Twenty-eight adult patients with AD were investigated regarding tachykinin expression in skin biopsies, using an immunohistochemical technique. The patients were characterized with clinical and psychodemographic parameters.

Results: The number of substance P and neurokinin (NK)A positive nerve fibers, as well as NKA positive mononuclear dermal cells, was increased in lesional compared to non-lesional skin. Interestingly, the depression score and the number of dermal NK-1 receptor (R) positive cells in lesional as well as in non-lesional skin showed a correlation.

Conclusion: These findings indicate an upregulation of the tachykinergic system in the inflamed skin of AD.     

Decreased Gene Expression of Epstein–Barr Virus-Induced Gene 3 (EBI-3) may Contribute to the Pathogenesis of Rheumatoid Arthritis

Background: Interleukin-35 (IL-35) is a member of the IL-12 family of heterodimeric cytokines produced by regulatory T (Treg) cells. This immunosuppressive cytokine can prevent exaggerated inflammatory responses like those responsible for the development of rheumatoid arthritis (RA). This study aims to determine the correlation between the gene expression of Epstein–Barr virus-induced gene 3 (EBI-3) and IL-12A (p35) subunits of IL-35 in peripheral blood leukocytes with immunological and clinical parameters in RA patients.

Methods: We recruited 47 patients with RA and 44 healthy subjects. The disease activity score-28 (DAS-28) was assessed by an expert rheumatologist and the plasma levels of neopterin and anti-cyclic citrullinated peptide (anti-CCP) was measured using ELISA method also Serum rheumatoid factor (RF) was assessed by the agglutination test. For the evaluation of IL-12A and EBI-3 gene expression, we used qPCR.

Results: We did not find any significant correlation between the gene expression of IL-35 subunits and DAS-28. There was a negative correlation between the plasma levels of neopterin and the gene expression of EBI-3 (p = 0.004). Inversely, we found a positive correlation between plasma level of anti-CCP and neopterin (p < 0.001) also between RF and DAS-28 (p = 0.001).

Conclusion: Regarding the significant negative correlation between EBI-3 gene expression and plasma levels of neopterin, it can be concluded that the altered gene expression of EBI-3 may play a role in the pathogenesis of RA.     

Abatacept for the treatment of rheumatoid arthritis

Introduction: Rheumatoid arthritis (RA) is a complex disease in which different mechanisms are involved. Studies suggest a key role for aberrant pathways of T-cell activation in the initiation and perpetuation of disease. Abatacept is a fusion protein composed of the Fc region of the immunoglobulin G1 (IgG1) fused to the extracellular domain of cytotoxic T lymphocyte-associated antigen (CTLA4). It has the ability to modulate T-cell activation by interfering with co-stimulation of these cells, a necessary step to become activated. This suggests that abatacept may play a role in the progression and/or even the initiation of RA.

Areas covered: a review of the different studies carried out during clinical development of abatacept was performed. Both formulations, intravenous (IV) and subcutaneous (SC), showed a similar and consistent efficacy and safety profile. Abatacept was effective both in RA patients not responding to methotrexate (MTX) and to tumor necrosis factor (TNF) inhibitors.

Expert commentary: abatacept, with its unique mechanism of action, proved to be a useful therapeutic alternative in RA, also having an acceptable safety profile. Evidence points out that abatacept may be able to alter the RA disease course. Ongoing studies will clarify this issue.     

A discussion of statistical methods to characterise early growth and its impact on bone mineral content later in childhood

Background: Many statistical methods are available to model longitudinal growth data and relate derived summary measures to later outcomes.

Aim: To apply and compare commonly used methods to a realistic scenario including pre- and postnatal data, missing data, and confounders.

Subjects and methods: Data were collected from 753 offspring in the Southampton Women’s Survey with measurements of bone mineral content (BMC) at age 6?years. Ultrasound measures included crown-rump length (11 weeks’ gestation) and femur length (19 and 34 weeks’ gestation); postnatally, infant length (birth, 6 and 12?months) and height (2 and 3?years) were measured. A residual growth model, two-stage multilevel linear spline model, joint multilevel linear spline model, SITAR and a growth mixture model were used to relate growth to 6-year BMC.

Results: Results from the residual growth, two-stage and joint multilevel linear spline models were most comparable: an increase in length at all ages was positively associated with BMC, the strongest association being with later growth. Both SITAR and the growth mixture model demonstrated that length was positively associated with BMC.

Conclusions: Similarities and differences in results from a variety of analytic strategies need to be understood in the context of each statistical methodology.     

Preclinical evidences of safety of a new synthetic adjuvant to formulate with the influenza human vaccine: absence of subchronic toxicity and mutagenicity

Context: Influenza is a severe, life-threatening viral disease that can be prevented by vaccination. However, the anti-influenza human vaccine failed to show the required efficacy both in infants under 5?years old and in the elder population, who are among those with the highest risk of developing severe complications after influenza infection. Therefore, it is of high importance to improve the vaccine efficacy and ensure its safety in these susceptible populations.

GK-1, a novel 18-aa peptide adjuvant, has been proved to increase the immunogenicity of the human influenza vaccine in both young and aged mice.

Objective: A preclinical study of the toxicity profile of GK-1 following the World Health Organization guidelines to support its use was herein conducted.

Material and methods: GK-1 was synthetically produced following Good Manufacturing Practices. The toxicological evaluation of GK-1 peptide was performed in rats after repeated dose-ranging trials by the subcutaneous route. The mutagenic potential of GK-1 was assessed by the micronucleus, chromosomal aberration, and Ames tests, in accordance with OECD Guidelines.

Results: GK-1 did not show toxic effects at doses up to 12.5mg/kg, corresponding to 25 times the dose intended for human use. No indications of mutagenic potential were observed. GK-1 after dermal administration was well tolerated locally.

Conclusion: The efficacy of GK-1 to improve influenza vaccine protection, along with the absence of toxicity and mutagenicity, as reported herein, support the evaluation of this peptide in a clinical trial as a novel adjuvant for human use.     

Differential effect of NDGA on cisplatin-induced nephrotoxicity in Spargue-Dawley rats

Context: Nephrotoxicity is a highly manifested complication in cancer patients undergoing cisplatin therapy. Oxidative stress, nitrosative stress, and inflammation are the major patho-mechanisms of cisplatin-induced nephrotoxicity.

Objective: The purpose of this study was to determine the protective effect of pretreatment and post-treatment of nordihydroguaiarectic acid (NDGA) on cisplatin-induced nephrotoxicity.

Material and methods: Cisplatin-induced renal damage was accessed by biochemical estimation of nephrotoxicity markers, oxidative and nitrosative stress whereas inflammatory markers were accessed by ELISA technique.

Results and conclusion: Cisplatin administration had resulted in renal injury associated with oxidative stress, nitrosative stress as evident by increased MDA, ROS, and nitrite level with decreased antioxidants such as SOD, catalase and, glutathione. Furthermore, cisplatin treated animals exhibited a noticeable pro-inflammatory response with the substantial increase in renal levels of TNF-α, IL-1β, and IL-6 and decrease in the renal level of IL-10. NDGA pretreatment did not lead to significantly rise in oxidative stress, nitrosative stress, and inflammation along with restored the level of IL-10 in the kidney and preserved renal function. Moreover, NDGA post-treatment also presented nephroprotective effects, but the effects were not as positive as compared to NDGA pretreatment. In conclusion, these results indicate that NDGA pretreatment is renoprotective while on the other hand NDGA post-treatment is not so effective in cisplatin-induced nephrotoxicity.     

Further Evidence for Embedded Performance Validity Tests in Children within the Conners’ Continuous Performance Test – Second Edition

Objective: To replicate previous research on Conners’ Continuous Performance Test – Second Edition subscales as performance validity tests (PVTs) in children.

Method: Classification accuracy for the Omissions (OMI), Hit Reaction Time (HRT), and Perseverations (PER) subscales was computed for 414 children and adolescents.

Results: Overall, OMI, HRT, and PER demonstrated good specificity but low and variable sensitivity across cutoffs.

Conclusions: Results suggest that OMI, HRT, and PER can function as embedded PVTs in mixed clinical samples of children, although their clinical utility is limited by their low sensitivity. Implications for the use of these PVTs in the context of attention-deficit/hyperactivity disorder evaluations, medication-seeking patients, and sports concussion clinics are discussed.     

Forensic characteristics and phylogenetic analysis of 23 Y-STR loci in the Miao population from Guizhou province,southwest China

Background: Investigation of haplotype/allele frequency data of Y-STR loci in ethnically diverse populations is essential for forensic reference database construction and genetic application. However, the population genetic characteristics of the Chinese Miao minority from Guizhou Province remain uncharacterised.

Aim: To assess forensic characteristics for 23 Y-Chromosomal STR loci in Guizhou Miao and explore population genetic relationships with geographically neighbouring populations.

Subjects and methods: Twenty-three Y-Chromosomal STRs were genotyped using the Powerplex^® Y23 system in 103 unrelated Chinese Miao males from Guizhou Province, southwest China. Haplotypes and forensic parameters were obtained. Population relationships of Guizhou Miao with others were revealed using AMOVA and an MDS plot.

Results: A total of 96 haplotypes were identified with overall haplotype diversity (HD) and discrimination capacity (DC) of 0.9985 and 0.9320, respectively. Genetic differentiation was observed with most of the comparison populations, prominently for Guizhou Shui.

Conclusion: The 23 Y-STR loci were highly polymorphic and discriminating in the Guizhou Miao population and could be used for forensic practice and population genetic studies. Population relationship analysis revealed Guizhou Miao had a close genetic relationship with geographically close Guizhou Gelao, as well as Han majorities derived from different regions.     

Survival of lymphocytes is not restricted by IDO-expressing fibroblast from rheumatoid arthritis patients

Objective: Rheumatoid arthritis (RA) is characterized by expansion of fibroblast-like synoviocytes (FLS) in inflamed joints and activation of lymphocytes. Tryptophan (trp) is an essential amino acid indispensable for the biosynthesis of proteins and critical for survival of lymphocytes. Indoleamine 2,3-dioxygenase (IDO) that initiates the degradation of trp and tryptophanyl-tRNA synthetase (TTS) essential for tryptophan synthesis, regulate trp bioavailability. Here, we tested the hypothesis that triggered by cytokines, enhanced IDO activity modulate regulatory function of otherwise non-tolerogenic FLS isolated from RA patients.

Materials and methods: IDO and TTS mRNA expression were evaluated by RT-PCR. IDO enzymatic activity was confirmed using HPLC. Resting or PHA-activated PBMC from healthy volunteers and RA patients were co-cultured with IDO expressing untreated (FLS_C) or IFNγ-treated (FLS_IFNγ) RA FLS. Lymphocyte survival and proliferation were evaluated by flow cytometry analysis and tritiated thymidine incorporation, respectively.

Results: RA FLS_IFNγ produce functionally active IDO and constitutively express TTS. RA FLS_C and FLS_IFNγ increased survival of resting lymphocytes in both studied groups, and decreased proliferation of healthy, but not RA, PBMC. Only FLS_IFNγ diminished survival of activated CD3⁺CD4^?, but not CD3⁺CD4⁺, healthy T cells and similar tendency was observed in rheumatoid cells. Importantly, IDO inhibitor, 1-methyl-DL-tryptophan (1-MT), failed to reverse this effect. PBMC, irrespective of their state (resting versus activated) or origin (healthy or RA), expressed high level of TTS mRNA.

Conclusions: We suggest that RA FLS express functionally active IDO but control survival and expansion of healthy cells in IDO-independent mechanism and exert weaker, if any, suppressive effect on rheumatoid cells.     

Disengagement and reengagement of HIV continuum of care in a single center cohort in northern Italy

Background: Despite the progress in HIV care, adherence to follow up remains critical. Disengagement impairs the benefit of HIV care and the increasing number of data that associates failed retention with worse outcomes has led public health institutions to consider retention in care as a new tool to fight against HIV pandemic.

Objective: The aim of this retrospective, observational study was to estimate the burden of disengagement and reengagement in care in our HIV cohort and to identify the characteristics of our LTFU and reengaged patients. Moreover, we build our cascade of care to explore how closely our center aligned with the “90–90–90” targets.

Methods: From the local electronic database we extracted all HIV-infected patients with at least one contact with HIV Clinic between 2012 and 2018 excluding deceased and transferred patients.

Our definition of LTFU was based on the lack of any visit during at least 1 year after the last visit. Patients re-engaged were defined as those firstly considered as LTFU patients who subsequently were newly linked to HIV care.

Results: About 8% of patients were lost to follow up during the period of study, with a rate of less than 2% per year and 14.1% of them were re-engaged in care. The cascade of care shows, among HIV cases diagnosed between 2011 and 2018, 86.7% patients retained in care, 94.1% of whom were on cART and 95.6% of whom were virologically suppressed.

A higher attrition was found among infections diagnosed since 2011 than before 2011, such as women, patients coming from foreign countries and those with poor virological control.

Conclusions: The retention rate found in our cohort is high and is in accordance with the 90–90–90 strategy. Nevertheless, understanding disengagement and re-engagement determinants is important to strengthen retention in care in the most fragile population.     

The role of IL-17 in systemic lupus erythematosus and its potential as a therapeutic target

Introduction: Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by autoantibodies production and immune complex deposition with systemic clinical manifestations. Interleukin (IL)-17-producing cells play a crucial role in disease pathogenesis and represent an attractive therapeutic target.

Areas covered: This review provides an update on the possibility of targeting IL-17 in SLE. The rational for this approach as well as currently available and future targets are discussed.

Expert opinion: Although human expression studies and animal models indicate that IL-17 blocking may be a promising therapeutic strategy for SLE, direct evidence for IL-17 inhibition in SLE patients is unavailable. Biologic therapies and small-molecule drugs that target IL-17 production are required for the achievement of a favorable clinical effect in SLE patients.     

The relationship between smoking,psoriasis and psoriatic arthritis

Introduction: Smoking is the single most important cause of preventable mortality worldwide. Besides being associated with major cardiovascular and bronchopulmonary diseases, and several cancers, it has been linked with a number of immune-related conditions, including psoriasis and psoriatic arthritis (PsA)

We aimed to summarize data on the role of smoking in the development and prognosis of psoriasis and PsA, pointing to the consequences in terms of disease management.

Areas covered: Mechanisms, clinical manifestations, and comorbidities associated with smoking in psoriasis and PsA were reviewed by searching Medline, Embase and Cochrane Library databases for papers published between January 2000 and July 2018 using combination of terms. Articles not written in English were excluded.

Expert commentary: Smoking is a risk factor for psoriasis development. As for PsA, smoking is positively associated with the disease at the population level, but it is negatively associated in patients with psoriasis. This phenomenon is referred to as the ‘smoking paradox’ of PsA. Smoking may cause poor response and reduced adherence to treatment of both psorasis and PsA. Physicians need to be aware of the smoking habits of their patients with psoriasis and PsA; whenever possible, smoking cessation programs should be considered.     

Adipokines in Multiple Sclerosis Patients with and without Optic Neuritis as the First Clinical Presentation

Background: Adipocytokines have been implied to be involved in multiple sclerosis (MS) pathogenesis. MS patients whose first clinical episode is optic neuritis (ON) have been reported to display a milder disease course. In this study, we aimed to show whether this milder disease course is related to reduced adipokine production.

Methods: A total of 55 (24 with ON as the first clinical episode) relapsing-remitting MS (RRMS) patients and 40 healthy individuals were recruited. Concentrations of adipokines were measured in sera by ELISA.

Results: The levels of adiponectin, leptin, resistin, monocyte chemoattractant protein-1 (MCP-1) and IL-8 were significantly higher in RRMS patients compared with healthy controls. RRMS cases starting with ON had lower expanded disability status scale scores. Serum adiponectin, leptin, resistin and MCP-1 levels were significantly lower in MS patients, whose first clinical episode was ON.

Conclusions: MS patients with ON as the first manifestation display both lower disability scores and reduced serum adipokine levels implying that adipocytokine production is associated with MS progression. Exact mechanisms of this association in MS patients with first episode ON need to be further studied.     

Maternal Serum sEndoglin and Cell-Free Fetal DNA as Probable Markers of Preeclampsia: A Study in Single Center,Egypt

Background: This study was conducted to compare the levels of maternal serum soluble endoglin (sEng) and cell-free fetal DNA (cffDNA) in pregnant females with PE to normotensive pregnant ones, together with relating these levels to preeclampsia (PE) severity and onset.

Method of the study: It was a comparative study in Mansoura University Hospital, Egypt, to detect the levels of serum sEng by ELISA besides the levels of cffDNA by quantitative real-time polymerase chain reaction in 80 pregnant females suffering from PE in addition to 80 normotensive pregnant ones that were included as control.

Results: Levels of serum sEng and cffDNA were higher in PE cases than control (p < 0.0001? both) and were significantly related to the severity of the disease. Levels were also higher in early than late onset PE (p < 0.003? and <0.002?, respectively). Sensitivities, specificities, positive, and negative predictive values in addition to accuracy of serum sEng and cffDNA were 97.5%, 98.8%, 98.7%, 97.5%, and 98.1% and 97.5%, 93.8%, 94.0%, 97.4%, and 95.6%, respectively.

Conclusion: Maternal serum sEng and cffDNA can be good markers for diagnosis of PE in Egyptian patients. They are positively related to the disease severity.

Abbreviations: cffDNA; Cell-Free Fetal DNA, sEng; soluble Endoglin, PE; preeclampsia, qRT PCR; Quantitative real-time polymerase chain reaction.     

Pain and affective distress in arthritis: relationship to immunity and inflammation

Introduction: Most arthritides are associated with pain and psychological distress (clinically significant depression and anxiety). Pain and depression are mutually exacerbating; both may continue even when joint involvement appears well controlled.

Area covered: There is strong evidence that arthritis-related stress impacts the central nervous system and, together with peripheral inflammatory changes, can cause central sensitization that can lead to chronic pain and worsening of affective distress. Cytokines and chemokines participate both in joint inflammation and in central sensitization. We review evidence of these relationships in five arthritides, namely rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, gout, and in osteoarthritis of the hips and knees. Central sensitization in these conditions results in long-lasting pain and psychological distress.

Expert commentary: Chronic pain and depression are important but often neglected in the clinical assessment and treatment of arthritis. The potential role of biologic cytokines and Janus kinase inhibitors in dealing with these symptoms needs further study.     

Effects of intermittent T-cell cluster disaggregation on proliferative capacity and checkpoint marker expression

Background/aim: T-cell immunotherapies are rapidly gaining grounds in clinical success. Presently, there is first-to-market knowledge on the translation of research scale methods to clinical and commercial scales. Improved understanding can lead to more consistent and efficient production, scaling, and eventual potency. T-cell checkpoint markers, proliferation, and T-cell cluster size and disaggregation are one set of parameters that have yet to be explored.

Methods: We herein activated T-cells and assessed various mechanical dissociation frequencies in relation to expression of checkpoint markers (measured by flow cytometry).

Results: We herein find increased T-cell proliferation capacity with increased dissociation frequency. We also find that with increased cluster size and duration, lower proliferation, and increased expression of checkpoint markers.

Conclusions: These findings reveal new translation findings with respect to T-cell handling and production and suggest that T-cell disaggregation may be important to improved cell yields and phenotype.     

Body language reading of emotion and outcome in schizophrenia

Introduction: Although considered a promising design for testing social cognition, it is not clear to what extent the EmoBio test of emotion recognition actually predicts community functioning. It is also not clear whether the test measures something unique or different from nonsocial cognition. The present study tests whether EmoBio accounts for GAF function score and two operationalised community outcome measures. The study also analyses cognitive predictors of EmoBio performance, testing whether stimulus modality affects prediction.

Methods: Eighty-three patients with schizophrenia were tested with EmoBio, the cognitive battery MCCB and WAIS-IV.

Results: EmoBio accounted for a significant portion of variance in all three outcome measures. Only EmoBio predicted Lifetime Relationship status, and EmoBio remained a significant predictor of Independent living beyond non-social cognition. All cognitive measures contributed significantly to the variance in EmoBio, but entered together explained only a third of total variance.

Conclusion: The study shows that emotion recognition accounts for community outcome. There was no clear effect of test-modality in predicting EmoBio performance, indicating no method invariance problem with EmoBio. It also indicates that the mechanisms underlying impaired social cognition in schizophrenia are different from the hypothesised non-verbal learning deficits in the disorder.     

Fluconazole induces genotoxicity in cultured human peripheral blood mononuclear cells via immunomodulation of TNF-α, IL-6, and IL-10: new challenges for safe therapeutic regimens

Context: Fluconazole (FNZ) is a drug used in antifungal therapy. However, the minimum FNZ dose to interfering with immune responses or inducing DNA damage is still unknown.

Objective: This study investigated the toxicological profile of FNZ on cultured human peripheral blood mononuclear cells (PBMCs) treated with different concentrations of this azole.

Materials and methods: Cultured PBMCs were exposed to FNZ (6, 12, 30, 60 and 120?μg/mL) and the toxicological profile was assessed by the following parameters: cytotoxic and nuclear division index (necrotic, apoptotic and viable cells), DNA damage (alkaline comet test), mutagenic potential (micronucleus test), cytokine modulation (IL-1, IL-6, IL-10, TNF-α, IFN-γ), and predictive toxicity (Osiris^® and LAZAR^® programs).

Results: Our results demonstrated that FNZ induced cellular DNA damage and mutagenicity at concentrations above the plasma peak (>30?μg/mL) and 6?μg/mL, respectively, which was associated with increased TNF-α, and decrease IL-6 and IL-10 concentrations. These effects may be related to increased apoptosis and cytotoxic nuclear division index in the cultured PBMCs. In silico results indicated potential mutagenic, tumorigenic, irritant, and carcinogenic effects, which were partially confirmed by the above assays.

Discussion and conclusions: Together, these findings suggest the need to rationalize the use of FNZ, especially if it is used for long periods or with concomitant pathologies requiring azole therapy that may increase FNZ's plasma concentration.     

Anti-DFS70 antibodies: an update on our current understanding and their clinical usefulness

Introduction: Anti-DFS70 antibodies and their clinical associations remain an immunological paradox. Unlike other antinuclear antibodies (ANA), there is a growing body of evidence that anti-DFS70 antibodies, when present in high titers and in isolation (without accompanying other antibodies), are useful to aid in the exclusion of ANA associated rheumatic diseases.

Areas covered: This review aims to analyze and interpret the current published knowledge and recent findings to provide guidance in the use of anti-DFS70 antibodies to analyze associations of this unique autoantibody.

Expert commentary: Although the association of anti-DFS70 antibodies is still unknown, their use as a biomarker that can aid in the exclusion of ANA related diseases is well-established.