Helically chiral NHC‐gold(I) complexes: synthesis, chiroptical properties and electronic features of the [5]helicene‐imidazolylidene ligand

The golden twist: Monodentate [5]helicene-imidazolylidene gold(I) complexes were prepared in good yields and structurally characterized. Benefiting from the presence of the configurationally stable [5]helicenic unit, they exhibit appealing chiroptical features, such as strong circular dichroism, moderate circularly polarized phosphorescence and dual emission with phosphorescence lifetimes up to the millisecond range

Synthesis, structural characterization, and chiroptical properties of planarly and axially chiral boranils

International audience2-Amino[2.2]paracyclophane reacts with salicylaldehyde or 2-hydroxyacetophenone to yield imines that then give access to a new series of boranils (8b–d) upon complexation with BF2. These novel boron-containing compounds display both planar and axial chiralities and were examined experimentally and computationally. In particular, their photophysical and chiroptical properties were studied and compared to newly prepared, simpler boranils (9a–d) exhibiting axial chirality only. Less sophisticated chiral architectures were shown to demonstrate overall stronger circularly polarized luminescence (CPL) activity

Racial differences in systemic sclerosis disease presentation: a European Scleroderma Trials and Research group study

Objectives. Racial factors play a significant role in SSc. We evaluated differences in SSc presentations between white patients (WP), Asian patients (AP) and black patients (BP) and analysed the effects of geographical locations.Methods. SSc characteristics of patients from the EUSTAR cohort were cross-sectionally compared across racial groups using survival and multiple logistic regression analyses.Results. The study included 9162 WP, 341 AP and 181 BP. AP developed the first non-RP feature faster than WP but slower than BP. AP were less frequently anti-centromere (ACA; odds ratio (OR) = 0.4, P < 0.001) and more frequently anti-topoisomerase-I autoantibodies (ATA) positive (OR = 1.2, P = 0.068), while BP were less likely to be ACA and ATA positive than were WP [OR(ACA) = 0.3, P < 0.001; OR(ATA) = 0.5, P = 0.020]. AP had less often (OR = 0.7, P = 0.06) and BP more often (OR = 2.7, P < 0.001) diffuse skin involvement than had WP.AP and BP were more likely to have pulmonary hypertension [OR(AP) = 2.6, P < 0.001; OR(BP) = 2.7, P = 0.03 vs WP] and a reduced forced vital capacity [OR(AP) = 2.5, P < 0.001; OR(BP) = 2.4, P < 0.004] than were WP. AP more often had an impaired diffusing capacity of the lung than had BP and WP [OR(AP vs BP) = 1.9, P = 0.038; OR(AP vs WP) = 2.4, P < 0.001]. After RP onset, AP and BP had a higher hazard to die than had WP [hazard ratio (HR) (AP) = 1.6, P = 0.011; HR(BP) = 2.1, P < 0.001].Conclusion. Compared with WP, and mostly independent of geographical location, AP have a faster and earlier disease onset with high prevalences of ATA, pulmonary hypertension and forced vital capacity impairment and higher mortality. BP had the fastest disease onset, a high prevalence of diffuse skin involvement and nominally the highest mortality

Identification of Novel Genetic Markers Associated with Clinical Phenotypes of Systemic Sclerosis through a Genome-Wide Association Strategy

Contains fulltext : 97006.pdf (publisher's version ) (Open Access)The aim of this study was to determine, through a genome-wide association study (GWAS), the genetic components contributing to different clinical sub-phenotypes of systemic sclerosis (SSc). We considered limited (lcSSc) and diffuse (dcSSc) cutaneous involvement, and the relationships with presence of the SSc-specific auto-antibodies, anti-centromere (ACA), and anti-topoisomerase I (ATA). Four GWAS cohorts, comprising 2,296 SSc patients and 5,171 healthy controls, were meta-analyzed looking for associations in the selected subgroups. Eighteen polymorphisms were further tested in nine independent cohorts comprising an additional 3,175 SSc patients and 4,971 controls. Conditional analysis for associated SNPs in the HLA region was performed to explore their independent association in antibody subgroups. Overall analysis showed that non-HLA polymorphism rs11642873 in IRF8 gene to be associated at GWAS level with lcSSc (P = 2.32x10(-12), OR = 0.75). Also, rs12540874 in GRB10 gene (P = 1.27 x 10(-6), OR = 1.15) and rs11047102 in SOX5 gene (P = 1.39x10(-7), OR = 1.36) showed a suggestive association with lcSSc and ACA subgroups respectively. In the HLA region, we observed highly associated allelic combinations in the HLA-DQB1 locus with ACA (P = 1.79x10(-61), OR = 2.48), in the HLA-DPA1/B1 loci with ATA (P = 4.57x10(-76), OR = 8.84), and in NOTCH4 with ACA P = 8.84x10(-21), OR = 0.55) and ATA (P = 1.14x10(-8), OR = 0.54). We have identified three new non-HLA genes (IRF8, GRB10, and SOX5) associated with SSc clinical and auto-antibody subgroups. Within the HLA region, HLA-DQB1, HLA-DPA1/B1, and NOTCH4 associations with SSc are likely confined to specific auto-antibodies. These data emphasize the differential genetic components of subphenotypes of SSc

Contributions to optimal care in systemic sclerosis

Systemic sclerosis (SSc) is a rare disease that preferentially affects females, with a reported female-to-male ratio of 4.6:1.0 and a typical onset between 45 and 64 years. The prevalence is difficult to evaluate and may well differ between countries and ethnicities. In France, the prevalence among adults is about 158/million. Thus, by extrapolation, the number of SSc cases in Belgium should be around 1,700. SSc is a multisystemic disease purportedly resulting from three types of injuries: fibrosis, immune dysregulation and vascular damage. The exact trigger and the precise relation between the three types of injuries are complex, remain incompletely understood and depend in part on extrinsic factors (such as environmental, viral or toxic factors) and genetic susceptibility. This disease is characterized by excessive production of extracellular matrix proteins by fibroblasts and the clinical picture mainly results from tissue fibrosis and vascular occlusions. Clinical manifestations are various but Raynaud’s phenomenon, digital ulcers, sclerodactyly, interstitial lung disease, oeso-gastro-intestinal hypotony, arthritis, myositis and pulmonary arterial hypertension are common symptoms. Mortality in some series of SSc is as high as 30% at 10 years. However, survival is variable due to disease heterogeneousness, impact of therapy, and difficulties in assessing the time of disease onset. There are only a few evidence-based drugs available in SSc. The lack of relevant animal models and the remaining uncertainties regarding pathophysiology largely explain this unmet need. Moreover, the rarity of the disease and the heterogeneous nature of the clinical manifestations limit the possibility to run randomized controlled trials. However, in 2009, recommendations for the treatment of SSc were published so that current treatment is based on expert opinions and on a patient-tailored multi-drug approach, according to the extent of skin/internal organ involvement. The Belgian Systemic Sclerosis Cohort (BSSC) is a nationwide initiative launched by Frédéric Houssiau in 2006. The aim of this long-term prospective observational study was to define the natural history of SSc, to identify prognostic factors, and, in parallel, to improve the quality of care. All prevalent and incident cases of SSc, fulfilling LeRoy and Medsger’s classification criteria followed in Belgian teaching hospitals were asked to participate. Data were collected in a prospective way, at baseline, 6 months and then yearly, within the regulatory frame required by good clinical practices. Since April 2006, 540 patients have been included. The first paper reports baseline and follow-up data on the first 438 patients included in the BSSC with a special emphasis on death rate and on correlations between disease severity scores, cutaneous subsets and autoantibody profile (paper 1). The BSSC is the backbone of this thesis; moreover, this large serie of well characterized cases gave us the opportunity to launch spin-off studies. First, we performed a study dealing with hand radiological damage in a large group of SSc patients, with a special emphasis on the distinction between osteoarthritic- and inflammation-driven damage. The originality of our work stems from the comparison with a gender- and age-matched control group and from the correlations we were able to test with the clinical and functional characteristics of SSc patients available through the BSSC (paper 2). Second, we developed and validated a questionnaire specifically aimed at testing manual ability of SSc patients. The latter was created using the Rasch model that estimates the item difficulty and the patient’s manual ability on a common linear scale from the answers given to each item, within a probablistic framework (paper 3). Third, in a small and retrospective study, we reported the safety, in terms of renal function and blood pressure, of monthly intravenous (IV) methylprednisolone (MP) pulses in early SSc patients suffering from interstitial lung disease (ILD), myositis, arthritis or rapidly progressing diffuse cutaneous involvement (paper 4). Finally, we suggested the efficacy and safety of mycophenolate mofetil combined to IV and oral glucocorticoids in a small one-year pilot study including 16 early SSc patients suffering from either interstitial lung disease or diffuse skin disease (paper 5).(MED 3) -- UCL, 201

Comparison of the disease activity score and the revised EUSTAR activity index in diffuse cutaneous systemic sclerosis patients.

OBJECTIVES: To compare the ability of the Disease Activity Score (DAS) and the Revised EUSTAR Activity Index (RAI) to detect diffuse cutaneous systemic sclerosis (dcSSc) patients requiring treatment intensification in a Belgian cohort. METHODS: We retrospectively compared the widely used DAS and the recently developed RAI in a longitudinal cohort (median follow-up of 42 months) of 62 dcSSc patients, of whom 30 with a disease duration ≤3 years at inclusion. Active disease was defined by a DAS ≥3/10 or a RAI ≥2.5/10. We chose a pragmatic definition to assess disease progression, namely any start or increase of glucocorticoids, immunosuppressants, anti-endothelin receptors or prostanoids. Sensitivity, specificity, negative and positive predictive values (NPV and PPV) of DAS and RAI for prediction of actual treatment changes were compared by ROC curves. RESULTS: According to RAI, 48% (of all dcSSc patients) and 55% (of ≤3 years dcSSc patients) were categorised as effectively active during follow-up while 34% and 43% according to DAS, respectively. The PPV and the NPV to detect disease progression, in ≤3 years dcSSc patients, were 59% and 89% for RAI vs 73% and 87% for DAS, respectively. The area under ROC curves were high for both scores (0.85 for RAI and 0.87 for DAS). CONCLUSIONS: Both scores are proven as predictive to detect disease activity, with a slightly better sensitivity for RAI. By contrast, RAI lacks specificity in predicting a real need for treatment intensification, thereby possibly leading to overtreatment

Hypercalcemia Heralding Pneumocystis jirovecii Pneumonia in an HIV-Seronegative Patient with Diffuse Cutaneous Systemic Sclerosis.

Pneumocystis pneumonia (PCP) is a life-threatening fungal infection occurring in immunocompromised patients such as HIV-positive patients with low CD4 cell count or patients under heavy immunosuppressive therapy. We report the case of a 59-year-old male with severe diffuse cutaneous systemic sclerosis presenting with asthenia, dry cough and worsening shortness of breath for the last 15 days. Biological studies were remarkable for PTH-independent severe hypercalcemia with low 25-hydroxyvitamin D and a paradoxically elevated 1,25-dihydroxyvitamin D. Early bronchoalveolar lavage allowed for PCP diagnosis and targeted treatment. We discuss the underlying physiopathology and difficulties regarding prophylaxis and treatment