Association between CD226 polymorphism and soluble levels in rheumatoid arthritis: Relationship with clinical activity

Objective: To study the relation between CD226 rs763361 gene polymorphism and CD226 serum level and to evaluate their role in susceptibility and disease activity of RA in a cohort of Egyptian individuals.

Methods: The serum level of CD226 was measured using a suitable ELISA kit and the CD226 rs763361 gene polymorphism was typed by PCR-RFLP for 112 RA patients and 100 healthy controls.

Results: Significant association with RA was found with CD226 T allele (OR (95%CI) = 1.6 (1.04–2.4), P = 0.032), and higher CD226 serum level (P = 0.001). Higher CD226 levels were associated with higher ESR values (P = 0.035), positive CRP (0.048), increased number of tender joints (P = 0.045), and higher DAS score (P = 0.035). Serum CD226 is an independent risk factor for the prediction of RA (P = 0.001). No correlations were found between the serum level of CD226 and different CD226 genotypes and also between them and RA activity grades.

Conclusion: The CD226 T allele may be susceptibility risk factors for the development of RA and the higher serum level of CD226 may be involved in the pathogenesis of RA in Egyptian patients. The serum level of CD226 and not CD226 genotypes could be considered as an independent risk factor for the prediction of RA within healthy individuals and also for RA disease activity.     

Study of the osteoprotegerin/receptor activator of nuclear factor-kB ligand system association with inflammation and atherosclerosis in systemic sclerosis

Objective: we aimed to study systemic sclerosis patients in order to assess osteoprotegerin/Receptor activator of nuclear factor-kB ligand (OPG/RANKL) system and find the relation of these biomarkers with the clinical features of the disease, the carotid intima thickness, markers of inflammation, lipid profile, and other laboratory characteristics.

Methods: both the level of (RANKL), (OPG) in sera of participants, in 30 (SSc) patients and the atherosclerotic changes affecting the common carotid artery were measured and, were compared to 30 healthy controls matched for age and sex. All participants were assessed clinically and subjected to the Revised Medsger SSc severity scale and underwent carotid Doppler ultrasound examination.

Results: OPG, RANKL, and RANKL/OPG were 1.9 ± 0.4 ng/ml, 24.3 ± 17.25 ng/ml, and 13.5 ±9.8 versus 0.77 ± 0.25 ng/ml, 7.13 ± 3.02 ng/ml, and 9.6 ± 3.1 in the SSc patients and the controls with significance (P = 0.001, P = 0.001, P = 0.045) respectively. The OPG- RANKL axis in the SSc patients correlated significantly with carotid intima thickness, arthritis, arthralgia, inflammatory markers, Medsger joint, Medsger vascular, Medsger skin, and dyslipidemia.

Conclusion: In cardiovascular risks, OPG serum level might increase as a preventive compensatory mechanism to neutralize the RANKL level increment. The determination of the OPG-RANKL system is a diagnostic indicator for the intensity of vascular calcification and atherosclerosis in SSc patients.     

Analysis of Helios gene expression and Foxp3 TSDR methylation in the newly diagnosed Rheumatoid Arthritis patients

Background: The control of auto-reactive cells is defective in rheumatoid arthritis (RA). Regulatory T (Treg) cells which play a key role in the modulation of immune responses have an impaired function in RA. Foxp3 is a master regulator of Treg cells which its expression is under the tight control of epigenetic mechanisms. In the current study, we analyzed the epigenetic modulation of the Foxp3 Treg-specific demethylated region (TSDR) and Helios gene expression to determine Treg cells alteration in RA patients.

Methods: We have recruited 20 newly diagnosed patients with RA and 41 healthy controls in our study. The measurement of Foxp3 and Helios gene expression was performed by the real-time PCR technique and the methylation level of TSDR was analyzed by bisulfite treatment and quantitative methylation-specific PCR (Q-MSP).

Results: We found that RA patients had significantly lower level of Foxp3 gene expression and TSDR demethylation compared to healthy subjects (P < 0.001 and P = 0.006, respectively). Inversely, the Helios gene expression was elevated significantly in RA patients group (P = 0.048). We also observed a significant correlation between Foxp3 and Helios gene expression (P = 0.016) as well as a significant correlation between FoxP3 expression and demethylation rate of TSDR (P = 0.010).

Conclusion: Our results suggested that both epigenetic modifications and Helios gene expression may have important roles in the pathogenesis of RA through their effects on Foxp3 gene expression.     

Immune Profiling of T Cells Infiltrating Vitreous Humor in Tubercular Uveitis

Purpose: To assess cellular composition and local cytokine response in vitreous humor of tubercular uveitis.

Methods: Cells were collected from vitreous cassettes and peripheral blood of 8 tubercular uveitis and 5 control subjects, undergoing vitrectomy and analyzed by flow cytometry for cellular composition, activation status, proinflammatory cytokine expression, and uptake of TLR9 ligand, CpG ODN 2216.

Results: CD3 + T cells with equal proportion of CD4+ and CD8 + T cells formed major fraction of infiltrating cells. The vitreous humor showed higher expression of recent activation marker, CD69, and proinflammatory cytokines, IFN-γ and IL-17A, in CD4 + T cells as compared to peripheral blood. Lastly, intraocular CD4 + T cells showed reduced uptake of ODN 2216 than peripheral blood.

Conclusions: Our results indicate that local antigenic stimuli trigger T cell infiltration and activation of CD4 + T cells that are hyporesponsive to TLR9 stimulation. These infiltrating T cells might be responsible in further aggravating ocular inflammation.     

Development and psychometric evaluation of a condom use self-efficacy measure in Spanish and English

Background: Condom self-efficacy is an important construct for HIV/STI prevention and intervention. A psychometrically sound measure of the self-efficacy for using condoms that has been designed for Hispanic women to respond in Spanish or English is needed.

Objectives: The goal of this study was to develop and evaluate a brief self-report measure of condom use self-efficacy.

Methods: We developed a 15-item measure of condom use self-efficacy based on expert knowledge of measurement and HIV/STI prevention with Hispanic women using a translation-back translation approach. Participants were 320 Hispanic women from the Southeastern US.

Results: Internal consistency of the full measure was 92. A short form of the instrument with a subset of five items also had acceptable internal consistency, alpha = .80, and was significantly correlated with the full scale, r_s = .93, p < .001. A single latent factor explained 9–48% of the variation in these items. Evidence of construct validity of the short form was provided by correlations of the scale with two self-report measures of condom use: r_s = .34** with condom use, r_s = .37** with condom use during vaginal sex.

Conclusions: Either the full measure or the five-item measure could be used in studies where condom use is an important behavioral outcome, such as evaluating prevention interventions, with Hispanic women. Future studies should examine the performance of this measure with other groups, including Hispanic men and members of other ethnic and language groups.     

Systematic overview of neuroanatomical differences in ADHD: Definitive evidence

Objectives: This article seeks to identify neuroanatomical differences in ADHD through an overview of systematic reviews that report encephalic differences compared to a control group in volume, area, activation likelihood or chemical composition.

Methods: We conducted a systematic search using Cochrane guidelines and PRISMA criteria in PubMed, Scopus, Web of Science, Cochrane Database of Systematic Reviews and Database of Abstracts of Reviews of Effects.

Results: Results revealed broad encephalic involvement that includes a functional frontal and cingulate hypoactivation and structural differences in corpus callosum, cerebellum and basal nuclei.

Conclusions: ADHD symptoms might be due to a multi-network unbalanced functioning hypothesis.     

Estimation of the elastic modulus of child cortical bone specimens via microindentation

Purpose: Non-pathological child cortical bone (NPCCB) studies can provide clinicians with vital information and insights. However, assessing the anisotropic elastic properties of NPCCB remains a challenge for the biomechanical engineering community. For the first time, this paper provides elastic moduli values for NPCCB specimens in two perpendicular directions (longitudinal and transverse) and for two different structural components of bone tissue (osteon and interstitial lamellae).

Materials and Methods: Microindentation is one of the reference methods used to measure bone stiffness. Here, 8 adult femurs (mean age 82 ± 8.9 years), 3 child femurs (mean age 13.3 ± 2.1 years), and 16 child fibulae (mean age 10.2 ± 3.9 years) were used to assess the elastic moduli of adult and child bones by microindentation.

Results: For adult specimens, the mean moduli measured in this study are 18.1 (2.6) GPa for osteons, 21.3 (2.3) GPa for interstitial lamellae, and 13.8 (1.7) GPa in the transverse direction.

For child femur specimens, the mean modulus is 14.1 (0.8) GPa for osteons, lower than that for interstitial lamellae: 15.5 (1.5) GPa. The mean modulus is 11.8 (0.7) GPa in the transverse direction. Child fibula specimens show a higher elastic modulus for interstitial lamellae 15.8 (1.5) than for osteons 13.5 (1.6), with 10.2 (1) GPa in the transverse direction.

Conclusion: For the first time, NPCCB elastic modulus values are provided in longitudinal and transverse directions at the microscale level.     

Associations between vitamin D receptor polymorphisms and susceptibility to Behcet’s disease: A meta-analysis

Background: The vitamin D receptor (VDR) gene polymorphisms have been reported to be related to the development of Behcet’s disease (BD). However, the results have been inconsistent among diverse populations. Therefore, this comprehensive meta-analysis has been designed to assess a more accurate association between VDR polymorphisms and BD susceptibility.

Methods: An electronic literature search was conducted to identify eligible studies. Pooled odds ratios (OR) with corresponding 95% confidence interval (CI) were calculated in different genetic models to assess this association.

Results: A total of six separate comparisons comprised of 468 cases and 516 controls were included in the meta-analysis model. The meta-result demonstrated that A allele of ApaI (A vs. a: 1.54 95% CI = 1.04–2.26, P = 0.029), and F allele of FokI (F vs. f: OR = 0.58, 95% CI = 0.45–0.76, P = 0.007) polymorphisms were associated with the risk of BD in total and African populations, respectively. This significant association was also found in recessive and homozygotes models. Subgroup analysis indicated that FokI variant among Africans and ApaI variant among Caucasian were significantly associated with the risk of BD. No relationship was found between Bsmi and TaqI polymorphisms and BD risk.

Conclusion: This meta-analysis demonstrated the association between FokI and ApaI polymorphisms in VDR gene with the risk of BD, providing insights into the potential role of vitamin D receptor in the pathogenesis of BD.     

A multi-site community randomized trial of community health workers to provide counseling and support for patients newly entering HIV care in rural Ethiopia: study design and baseline implementation

Background: Although HIV therapy is delivered to millions globally, treatment default (especially soon after entering care) remains a challenge. Community health workers (CHWs) can provide many services for people with HIV, including in rural and resource-limited settings.

Objectives: We designed and implemented a 32 site community randomized trial throughout southern Ethiopia to assess an intervention using CHWs to improve retention in HIV care.

Methods: Sixteen district hospital and 16 local health center HIV clinics were randomized 1:1 to be intervention or control sites. From each site, we enrolled adults newly entering HIV care. Participants at intervention sites were assigned a CHW who provided: HIV and health education; counseling and social support; and facilitated communication with HIV clinics. All participants are followed through three years with annual health surveys, plus HIV clinic record abstraction including clinic visit dates. CHWs record operational data about their client contacts.

Results: 1799 HIV patients meeting inclusion criteria were enrolled and randomized: 59% were female, median age = 32 years, median CD4 + count = 263 cells/mm³, and 41% were WHO Stage III or IV. A major enrollment challenge was fewer new HIV patients initiating care at participating sites due to shortage of HIV test kits. At intervention sites, 71 CHWs were hired, trained and assigned to clients. In meeting with clients, CHWs needed to accommodate to various challenges, including HIV stigma, distance, and clients lacking cell phones.

Conclusions: This randomized community HIV trial using CHWs in a resource-limited setting was successfully launched, but required flexibility to adapt to unforeseen challenges.     

Pregnane X Receptor Polymorphisms and Risk of Inflammatory Bowel Disease: A Meta-Analysis

Background: Pregnane X receptor (PXR) gene polymorphisms have been widely studied in terms of the association with inflammatory bowel disease (IBD), with inconsistent results.

Objective: The present meta-analysis was performed to assess the association between PXR gene polymorphisms and the susceptibility of IBD, Crohn’s disease (CD), and ulcerative colitis (UC).

Methods: PubMed, Wanfang, and CNKI databases were searched for eligible studies before November 1, 2016. Pooled odds ratios (ORs) and 95% confidence intervals (95% CIs) were used to calculate the various genetic models using either a fixed-effect or a random-effect model. The heterogeneity of the included studies was examined with Cochran Q and I² statistics. Begg’s rank correlation test and Egger’s linear regression test were used to assess the publication bias.

Results: A total of six studies with 4248 cases and 3853 controls were included in this meta-analysis. Three PXR gene polymorphisms were evaluated: rs1523127, rs2276707, and rs6785049. Our analyses of rs1523127, rs2276707, and rs6785049 suggested that PXR gene polymorphism had no obvious influence on the risk of IBD in Caucasians. Subgroup analyses based on disease type showed similar results.

Conclusion: Our meta-analysis revealed that PXR gene polymorphism may not be significantly associated with IBD susceptibility. However, the number of original studies was limited and further studies with large samples are needed to verify the results.

Abbreviations: PXR = pregnane X receptor, IBD = inflammatory bowel disease, CD = Crohn’s disease, UC = ulcerative colitis, ORs = pooled odds ratios, 95% CIs = 95% confidence intervals, NOS = Newcastle–Ottawa scale, HWE = Hardy–Weinberg equilibrium.     

Update of sarilumb to treat rheumatoid arthritis based on randomized clinical trials: a systematic review

Introduction: Sarilumab is a human monoclonal antibody against Interleukin 6 α (IL-6α) receptor. Compared to tocilizumab, another IL-6 α receptor antibody, sarilumab has a different structure and higher affinity.

Areas covered: In a systematic literature review, we examined all sarilumab randomized clinical trials (RCTs) in rheumatoid arthritis. The 6 reviewed RCTs included patients who were inadequate MTX, DMARD and/or TNFi responders. Sarilumab 150–200 mg every 2 weeks improved RA signs, symptoms, function and decreased radiological progression up to 52 weeks. The most common adverse events were infections and neutropenia, the latter of which will require careful observation in future trials.

Examination of the effect of sero-positivity, disease duration, presence of erosions, use of previous biologic and comparisons to other biologics etc are still needed to complete understanding of this drug’s profile. Long term studies, too, will be needed to assess long term tolerability

Expert commentary: Results support the use of sarilumab to treat RA patients with inadequate response to MTX, other DMARDs and TNFis, although further studies are needed to fully assess its toxicity and understand the specific place of sarilumab in the RA armamentarium.     

Intra-articular treatment with corticosteroids increases apoptosis in human rotator cuff tears

Purpose: The aim of this study is to evaluate in vivo the level of apoptosis in human rotator cuff tears and the relationship it might have with tendon degeneration.

Methods: Rotator cuff biopsies from 19 male and female patients, ages between 38 and 68 years, with and without previous corticosteroid infiltrations were collected via arthroscopy. Biopsies from seven patients with healthy rotator cuffs were used as a control group. An in situ terminal deoxynucleotidyl transferase dUTP nick end labeling assay was performed to detect the level of apoptosis, which was expressed as a percentage of apoptotic cells (PAC).

Results: PAC in patients with corticosteroid infiltrations was 76.97 ± 16.99 in all tendon rupture zones, in non-infiltrated patients was 35.89 ± 22.96, whereas in control patients was 14.48 ± 8.15. Likewise, the tendency of PAC reveals that apoptosis in control and non-infiltrated groups was different and dispersed in all tear zones; while in corticosteroid treated patients, the tendency was similar in all rupture sites.

Conclusions: This investigation leads us to conclude that the administration of corticosteroid is associated with a higher amount of apoptosis at the insertion site of the rotator cuff (rupture edge).     

Topical immunotherapy with diphencyprone (DPCP) for in-transit and unresectable cutaneous melanoma lesions: an inaugural Canadian series

Background: Diphencycprone (DPCP) is an immune contact sensitizer applied to melanoma lesions. Early studies show favorable efficacy. We present the first North-American series of patients treated with DPCP.

Methods: A single center retrospective study of patients with in-transit or unresectable melanoma lesions treated with DPCP from December 1,2014 to December 31,2015 was completed. Primary objectives were response rate and toxicity. Secondary objective was health-related quality of life assessment with the Functional Assessment of Cancer Therapy-Melanoma (FACT-M) questionnaire.

Results: Fifteen consecutive patients were identified with median age of 78 (range 43–92). 73% of patients had prior treatment. Two patients (13%) had a complete response after 25 and 32 weeks, respectively. Four patients (27%) had a partial response with a mean treatment time of 30 weeks (range 6–51 weeks). Six (40%) had stable disease. Six patients stopped DPCP – three from systemic progression and three from toxicity. The most common toxicity was blisters; one patient had significant skin ulceration that resolved on stopping DPCP. Median FACT-M score was 142.95 (possible total 172). Mean overall follow-up time was 22.7 weeks.

Conclusion: DPCP is a feasible option for in-transit and other melanoma cutaneous lesions ineligible/refractory to surgery and may delay need for systemic therapy.     

Matrix Metalloproteinase-9 rs17576 Gene Polymorphism and Behçet’s Disease: Is There an Association?

Background: Clinical studies have reported a significant association between matrix metalloproteinases (MMP), particularly (MMP-9), and inflammatory diseases including Behçet’s disease (BD).

Purpose: To study the relationship between MMP-9 rs17576 gene polymorphism and the development of BD, and its relation to disease activity among Egyptian patients.

Methods: A total of 100 BD patients and 100 healthy control volunteers were genotyped for MMP-9 rs17576 polymorphism with polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), followed by the confirmation of our results in random subgroups using direct DNA sequencing technique.

Results: The frequency of the GG genotype and G allele was significantly higher in BD patients as compared to the normal controls (p = 0.011, OR 8.61; p = 0.03, OR 1.65, respectively). There was no significant association between the MMP-9 rs17576 polymorphism and the clinical outcomes of BD.

Conclusion: our study suggests a significant association of the MMP-9 rs17576 A/G polymorphism with increased risk of BD development in Egyptian patients.     

ALK protein expression in pulmonary adenocarcinoma of Tunisian patients

Background. It is now necessary to determine ALK status in order to use targeted therapy. Aim: herein, we assess immunohistochemical profile of ALK protein in a series of Tunisian patients with pulmonary adenocarcinoma.

Materials and Methods. ALK protein expression was studied applying the D5F3 antibody with a fully automated Ventana CDx technique on a series of 19 patients.

Results. Positive ALK expression was found in one case (5.2%) corresponding to a papillary adenocarcinoma which showed a strong granular and homogenous cytoplasmic staining. The patient was a 30-years-old woman.

Conclusion. The frequency of positive ALK expression based on immunohistochemistry in our series was similar to that reported in the world literature.     

Do patients with different psychiatric disorders show altered social decision-making? A systematic review of ultimatum game experiments in clinical populations

Background: Impairments in social functioning are a common feature of psychiatric disorders. Game paradigms pose a unique way for studying how people make decisions in interpersonal contexts. In the last decade, researchers have started to use these paradigms to study social decision-making in patients with psychiatric disorders.

Purpose: The aim of this systematic literature review is to summarise the currently available evidence on the behaviour of patients with psychiatric disorders in the commonly used Ultimatum Game (UG).

Method: A systematic literature search including MEDLINE, PsycINFO, PSYNDEXplus Tests, PSYNDEXPLUS Literature, EBM Reviews—Cochrane Central Register of Controlled Trials, Embase and PASCAL was performed via the Ovid interface.

Results: We found evidence for alterations in UG behaviour for patients with frontotemporal dementia, schizophrenia, affective disorders, alcohol, cocaine, heroin and 3,4-methylenedioxymethamphetamine consumption, alcohol dependence, anxiety disorders, borderline personality disorder, autism, Tourette syndrome and oppositional defiant disorder.

Conclusion: There is some evidence that different psychiatric disorders might go along with alterations in social decision-making. However, in general, data are currently limited and studies are hard to compare due to differences in methodologies.     

Virologic outcomes in early antiretroviral treatment: HPTN 052

Introduction: The HIV Prevention Trials Network (HPTN) 052 trial demonstrated that early antiretroviral therapy (ART) prevented 93% of HIV transmission events in serodiscordant couples. Some linked infections were observed shortly after ART initiation or after virologic failure.

Objective: To evaluate factors associated with time to viral suppression and virologic failure in participants who initiated ART in HPTN 052.

Methods: 1566 participants who had a viral load (VL) > 400 copies/mL at enrollment were included in the analyses. This included 832 in the early ART arm (CD4 350–550 cells/mm³ at ART initiation) and 734 in the delayed ART arm (204 with a CD4 < 250 cells/mm³ at ART initiation; 530 with any CD4 at ART initiation). Viral suppression was defined as two consecutive VLs ≤ 400 copies/mL after ART initiation; virologic failure was defined as two consecutive VLs > 1000 copies/mL > 24 weeks after ART initiation.

Results: Overall, 93% of participants achieved viral suppression by 12 months. The annual incidence of virologic failure was 3.6%. Virologic outcomes were similar in the two study arms. Longer time to viral suppression was associated with younger age, higher VL at ART initiation, and region (Africa vs. Asia). Virologic failure was strongly associated with younger age, lower educational level, and lack of suppression by three months; lower VL and higher CD4 at ART initiation were also associated with virologic failure.

Conclusions: Several clinical and demographic factors were identified that were associated with longer time to viral suppression and virologic failure. Recognition of these factors may help optimize ART for HIV treatment and prevention.