Right Ventricular Function Evolution With Pregnancy in Repaired Tetralogy of Fallot

This case illustrates the evolution of right ventricular (RV) 3-dimensional (3D) area strain during pregnancy in a patient with repaired Tetralogy of Fallot. The report highlights impairment in RV function with pregnancy, suggesting the importance of prepregnancy RV systolic function assessment, especially using 3D echocardiography.     

Drug-induced vitiligo: a case/non-case study in Vigibase®, the WHO pharmacovigilance database

Vitiligo is a common depigmenting disorder ensuing the loss of epidermal melanocytes. It is a multifactorial disease with immunological, genetic and environmental factors including drug exposure. The purpose of the study was to investigate the drugs and therapeutic subclasses associated with vitiligo occurrence reported in VigiBase^®, the WHO pharmacovigilance database. A case/non-case study was carried out by defining cases as vitiligo reports and non-cases as all other reports. The reporting odds ratio (ROR) was calculated for the ‘suspected’ drugs and drug classes according to ATC level 4. During the study period, 741 cases of vitiligo were registered. Mean age was 49 ± 20 years. The disproportionality analysis showed an association between vitiligo and pembrolizumab (ROR 116.9, 95% Confidence Interval (CI) 94.8, 144.3), nivolumab (ROR 22.6, 95% CI 15.8, 32.4), ipilimumab (ROR 41.7, 95% CI 25.0, 69.7), imiquimod (ROR 152.8, 95% CI 103.0, 226.7), adalimumab (ROR 3.8, 95% CI 2.5,5.8), infliximab (ROR 2.6, 95% CI 1.65, 4.01), alemtuzumab (ROR 27.8, 95% CI 17.6, 43.9), and ustekinumab (ROR 9.3, 95% CI 5.6, 15.6). Concerning the pharmacological classes ATC level 4, a significant association was found with monoclonal antibodies, interferons, selective immunosuppressants, TNF-alpha inhibitors, interleukin inhibitors, and topical antivirals. This study confirmed the expected associations between vitiligo and immune checkpoint inhibitors and strengthened the emerging signal about the association between vitiligo and imiquimod, TNF-alpha inhibitors and interferons. New signals were shown with selective immunosuppressants including alemtuzumab and interleukin inhibitors.     

Telaprevir- and boceprevir-based tritherapies in real practice for F3-F4 pretreated hepatitis C virus patients

AIM:To assess,in a routine practice setting,the sus-tained virologic response(SVR) to telaprevir(TPV) or boceprevir(BOC) in hepatitis C virus(HCV) nullresponders or relapsers with severe liver fibrosis.METHODS:One hundred twenty-five patients were treated prospectively for 48 wk with TPV or BOC + pegylated-interferon(peg-INF) α2a + ribavirin(PR) according to standard treatment schedules without randomization.These patients were treated in routine practice settings in 10 public or private health care centers,and the data were prospectively collected.Only patients with severe liver fibrosis(Metavir scores of F3 or F4 upon liver biopsy or liver stiffness assessed by elastography),genotype 1 HCV and who were null-responders or relapsers to prior PR combination therapy were included in this study.RESULTS:The Metavir fibrosis scores were F3 in 35(28%) and F4 in 90(72%) of the patients.In total,62.9% of the patients were null-responders and 37.1% relapsers to the previous PR therapy.The overall SVR rate at 24 wk post-treatment withdrawal was 59.8%.The SVR was 65.9% in the TPV group and 44.1% in the BOC group.Independent predictive factors of an SVR included a response to previous treatment,relapsers vs null-responders [OR = 3.9;(1.4,10.6),P = 0.0084],a rapid virological response(RVR) [OR 6.9(2.6,18.2),P = 0.001] and liver stiffness lower than 21.3 kPa [OR = 8.2(2.3,29.5),P = 0.001].During treatment,63 patients(50.8%) had at least one severe adverse event(SAE) of grade 3 or 4.A multivariate analysis identified two factors associated with SAEs:female gender [OR = 2.4(1.1,5.6),P = 0.037] and a platelet count below 150 × 103/ mm3 [OR = 5.3(2.3,12.4),P ≤ 0.001].CONCLUSION:More than half of these difficult-to-treat patients achieved an SVR and had SAEs in an actual practice setting.The SVR rate was influenced by the response to previous PR treatment,the RVR and liver stiffness.     

The effect of antigen deprivation on thymus-dependent and thymus-independent lymphocytes in the small intestine of the mouse

Isografts of foetal small intestine, implanted under the kidney capsules of adult mice grow normally and, despite the lack of intraluminal antigenic stimulation, are populated by thymus-dependent and thymus-independent lymphocytes. The Peyer's patches in these grafts are very small, lack germinal centres and can be shown to have small thymus-dependent areas.

Quantitative intraepithelial lymphocyte counts were carried out in normally sited small intestine of immunologically intact and thymus-deprived mice, and in grafts implanted in intact and thymus-deprived mice. Counts were also performed in a group of neonatally thymectomized and control mice. The results show a significant depletion of intraepithelial lymphocytes in neonatally thymectomized mice, and a profound reduction in numbers of intraepithelial lymphocytes in grafts, deprived of antigen, when compared with normally sited intestine of the same age.

     

Toxoplasma gondii infection can regulate the expression of tumour necrosis factor-alpha receptors on human cells in vitro

The in vitro regulation of tumour necrosis factor (TNF)-alpha receptors during Toxoplasma gondii infection of human MRC5 fibroblasts and human myelomonocytic THP-1 cells was investigated. Cells were infected with the virulent RH of T. gondii. TNFR membrane receptors were analysed by flow cytometry with biotinylated TNF-alpha. Shedding of the soluble form of TNFR1 and TNFR2 in cell culture supernatants was measured by enzyme-linked immunosorbent assay, and expression of mRNA production of TNFR1 and TNFR2 was analysed by quantitative real-time polymerase chain reaction, 1 h after infection. In the MRC5 cell line, T. gondii infection did not induce any up- or down-regulation of membrane TNFRs, soluble TNFRs or mRNA of TNFRs. However, THP-1 cell infection with living parasites induced a significant soluble TNFR1 release by THP-1 cells after 1 h. We detected an approximately 50% up-regulation (P < 0.01) of soluble TNFR1 in infected THP-1 cells compared to controls. No change in soluble TNFR2 levels was observed in the same conditions. Moreover, infection decreased the level of TNF membrane receptors, but had no effect on TNFR1 and TNFR2 mRNA levels. TNFR modulation by T. gondii infection, in vitro, depends on the cell type. Furthermore, our data suggest that living parasites control the shedding of the soluble form of TNFR1. This mechanism may influence the role of TNF-alpha in toxoplasmosis.     

WHIM syndromes with different genetic anomalies are accounted for by impaired CXCR4 desensitization to CXCL12

The WHIM syndrome is a rare immunodeficiency disorder characterized by warts, hypogammaglobulinemia, infections, and myelokathexis. Dominant heterozygous mutations of the gene encoding CXCR4, a G-protein-coupled receptor with a unique ligand, CXCL12, have been associated with this pathology. We studied patients belonging to 3 different pedigrees. Two siblings inherited a CXCR4 mutation encoding a novel C-terminally truncated receptor. Two unrelated patients were found to bear a wild-type CXCR4 open reading frame. Circulating lymphocytes and neutrophils from all patients displayed similar functional alterations of CXCR4-mediated responses featured by a marked enhancement of G-protein-dependent responses. This phenomenon relies on the refractoriness of CXCR4 to be both desensitized and internalized in response to CXCL12. Therefore, the aberrant dysfunction of the CXCR4-mediated signaling constitutes a common biologic trait of WHIM syndromes with different causative genetic anomalies. Responses to other chemokines, namely CCL4, CCL5, and CCL21, were preserved, suggesting that, in clinical forms associated with a wild-type CXCR4 open reading frame, the genetic anomaly might target an effector with some degree of selectivity for the CXCL12/CXCR4 axis. We propose that the sustained CXCR4 activity in patient cells accounts for the immune-hematologic clinical manifestations and the profusion of warts characteristic of the WHIM syndrome.