Primary systemic sclerosis heart involvement: A systematic literature review and preliminary data-driven, consensus-based WSF/HFA definition

Introduction: Primary heart involvement in systemic sclerosis may cause morpho-functional and electrical cardiac abnormalities and is a common cause of death. The absence of a clear definition of primary heart involvement in systemic sclerosis limits our understanding and ability to focus on clinical research. We aimed to create an expert consensus definition for primary heart involvement in systemic sclerosis. Methods: A systematic literature review of cardiac involvement and manifestations in systemic sclerosis was conducted to inform an international and multi-disciplinary task force. In addition, the nominal group technique was used to derive a definition that was then subject to voting. A total of 16 clinical cases were evaluated to test face validity, feasibility, reliability and criterion validity of the newly created definition. Results: In total, 171 publications met eligibility criteria. Using the nominal group technique, experts added their opinion, provided statements to consider and ranked them to create the consensus definition, which received 100% agreement on face validity. A median 60(5–300) seconds was taken for the feasibility on a single case. Inter-rater agreement was moderate (mKappa (95% CI) = 0.56 (0.46–1.00) for the first round and 0.55 (0.44–1.00) for the second round) and intra-rater agreement was good (mKappa (95% CI) = 0.77 (0.47–1.00)). Criterion validity showed a 78 (73–84)% correctness versus gold standard. Conclusion: A preliminary primary heart involvement in systemic sclerosis consensus-based definition was created and partially validated, for use in future clinical research

Activation of endogenous p53 by combined p19Arf gene transfer and nutlin-3 drug treatment modalities in the murine cell lines B16 and C6

<p>Abstract</p> <p>Background</p> <p>Reactivation of p53 by either gene transfer or pharmacologic approaches may compensate for loss of p19Arf or excess mdm2 expression, common events in melanoma and glioma. In our previous work, we constructed the pCLPG retroviral vector where transgene expression is controlled by p53 through a p53-responsive promoter. The use of this vector to introduce p19Arf into tumor cells that harbor p53wt should yield viral expression of p19Arf which, in turn, would activate the endogenous p53 and result in enhanced vector expression and tumor suppression. Since nutlin-3 can activate p53 by blocking its interaction with mdm2, we explored the possibility that the combination of p19Arf gene transfer and nutlin-3 drug treatment may provide an additive benefit in stimulating p53 function.</p> <p>Methods</p> <p>B16 (mouse melanoma) and C6 (rat glioma) cell lines, which harbor p53wt, were transduced with pCLPGp19 and these were additionally treated with nutlin-3 or the DNA damaging agent, doxorubicin. Viral expression was confirmed by Western, Northern and immunofluorescence assays. p53 function was assessed by reporter gene activity provided by a p53-responsive construct. Alterations in proliferation and viability were measured by colony formation, growth curve, cell cycle and MTT assays. In an animal model, B16 cells were treated with the pCLPGp19 virus and/or drugs before subcutaneous injection in C57BL/6 mice, observation of tumor progression and histopathologic analyses.</p> <p>Results</p> <p>Here we show that the functional activation of endogenous p53wt in B16 was particularly challenging, but accomplished when combined gene transfer and drug treatments were applied, resulting in increased transactivation by p53, marked cell cycle alteration and reduced viability in culture. In an animal model, B16 cells treated with both p19Arf and nutlin-3 yielded increased necrosis and decreased BrdU marking. In comparison, C6 cells were quite susceptible to either treatment, yet p53 was further activated by the combination of p19Arf and nutlin-3.</p> <p>Conclusions</p> <p>To the best of our knowledge, this is the first study to apply both p19Arf and nutlin-3 for the stimulation of p53 activity. These results support the notion that a p53 responsive vector may prove to be an interesting gene transfer tool, especially when combined with p53-activating agents, for the treatment of tumors that retain wild-type p53.</p

Transitional Care for Patients with Congenital Colorectal Diseases: An EUPSA Network Office, ERNICA, and eUROGEN Joint Venture

Background: Transition of care (TOC; from childhood into adulthood) of patients with anorectal malformations (ARM) and Hirschsprung disease (HD) ensures continuation of care for these patients. The aim of this international study was to assess the current status of TOC and adult care (AC) programs for patients with ARM and HD. Methods: A survey was developed by members of EUPSA, ERN eUROGEN, and ERNICA, including patient representatives (ePAGs), comprising of four domains: general information, general questions about transition to adulthood, and disease-specific questions regarding TOC and AC programs. Recruitment of centres was done by the ERNs and EUPSA, using mailing lists and social media accounts. Only descriptive statistics were reported. Results: In total, 82 centres from 21 different countries entered the survey. Approximately half of them were ERN network members. Seventy-two centres (87.8%) had a self-reported area of expertise for both ARM and HD. Specific TOC programs were installed in 44% of the centres and AC programs in 31% of these centres. When comparing centres, wide variation was observed in the content of the programs. Conclusion: Despite the awareness of the importance of TOC and AC programs, these programs were installed in less than 50% of the participating centres. Various transition and AC programs were applied, with considerable heterogeneity in implementation, content and responsible caregivers involved. Sharing best practice examples and taking into account local and National Health Care Programs might lead to a better continuation of care in the future. Level of Evidence: III

Structural investigations of 5-hydroxy-4,5-dihydroisoxazoles

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)The X-ray diffraction data determined for eight 3-(R-3), 4-(R-4), 4,4-(R-4/R-4') and/or 5-(R-5) 5-hydroxy-4,5-dihydroisoxazoles [where R-3 = Ph, R-4/R-4' = H/H, R-5 = CCl3 (1); R-3 = 4-Br-C6H4, R-4/R-4' = H/H, R-5 = CCl3 (2); R-3 = thien-2-yl, R-4/R-4' = H/H, R-5 = CCl3 (3); R-3 = Ph, R-4 = Ph, R-4' = OH, R-5 = Me (4); R-3 = Me, R-4/R-4' = N-OH, R-5 = Me (5); R-3 = CF3, R-4/R-4' = H/H, R-5 = CMe2CH2OH (6); R-3 = H, R-4 = 4-I-C6H4, R-4' = H, R-5 = 4-I-C6H4 (7): R-3/R-4 = -(CH2)(3)-, R-4' = H, R-5 = CF2CF2H (8);] are discussed. The crystalline structure of compounds 1-3 is described for the first time and crystalline structure of compounds 4-8 has already been described in literature. It was found that the supramolecular auto-organization of 1-8 is characterized by hydrogen bonds invariably involving the hemiacetal hydroxyl group. Compound 5 is the only exception, where the hydroxyl oxime group is the participant in the hydrogen bond. Compounds 4 and 8 present intermolecular contact between the hydroxyl group of the hemiacetal and the nitrogen atom of the 4,5-dihydroisoxazole ring. Compound 7 presents similar interaction, where the hydroxyl contact is with the oxygen atom of the 4,5-dihydroisoxazole ring. Moreover, the crystal structure of compound 6 was stabilized by O-H center dot center dot center dot O interaction between the hydroxyl group of hemiacetal and the hydroxyl group of the alcohol function attached at the 5-position of 4,5-dihydroisoxazole. The crystal structure of compounds 1-3, as described here for the first time, was similar to that of compounds 4 and 7, showing a hydrogen bond O(51)-H(51)center dot center dot center dot N(2) between the hydroxyl group and the nitrogen atom of the isoxazoline ring. This means that the crystal structure of these compounds was governed by hydrogen bonds O-H center dot center dot center dot N, involving the hydroxyl of the hemiacetal group and the nitrogen atom of the 4,5-dihydroisoxazole ring. This interaction is relatively robust, showing a pattern in the crystal packing. Compounds 1-3 also have their crystal stabilized by more weak interactions of type Cl center dot center dot center dot Cl, involving the chlorine atom of the trichloromethyl group. (C) 2011 Elsevier B.V. All rights reserved.100641699462468Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundacao de Amparo a Pesquisa do Estado do Rio Grande do Sul - FAPERGS [PRONEX/Proc. 10/0037-8]Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)FAPERGSConselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)CNPq [Universal/Proc. 485893/2007-0, Universal/Proc. 471519/2009-0, MAPA/Proc. 578426/2008-0]Fundacao de Amparo a Pesquisa do Estado do Rio Grande do Sul - FAPERGS [PRONEX/Proc. 10/0037-8]CAPES [PRODOC/Proc. 2684-32/2010

The clinical phenotype of systemic sclerosis patients with anti-PM/Scl antibodies: results from the EUSTAR cohort

To evaluate clinical associations of anti-PM/Scl antibodies in patients with SSc in a multicentre international cohort, with particular focus on unresolved issues, including scleroderma renal crisis (RC), malignancies, and functional outcome of interstitial lung disease (ILD)

Primary systemic sclerosis heart involvement: A systematic literature review and preliminary data-driven, consensus-based WSF/HFA definition

Introduction: Primary heart involvement in systemic sclerosis may cause morpho-functional and electrical cardiac abnormalities and is a common cause of death. The absence of a clear definition of primary heart involvement in systemic sclerosis limits our understanding and ability to focus on clinical research. We aimed to create an expert consensus definition for primary heart involvement in systemic sclerosis. Methods: A systematic literature review of cardiac involvement and manifestations in systemic sclerosis was conducted to inform an international and multi-disciplinary task force. In addition, the nominal group technique was used to derive a definition that was then subject to voting. A total of 16 clinical cases were evaluated to test face validity, feasibility, reliability and criterion validity of the newly created definition. Results: In total, 171 publications met eligibility criteria. Using the nominal group technique, experts added their opinion, provided statements to consider and ranked them to create the consensus definition, which received 100% agreement on face validity. A median 60(5–300) seconds was taken for the feasibility on a single case. Inter-rater agreement was moderate (mKappa (95% CI) = 0.56 (0.46–1.00) for the first round and 0.55 (0.44–1.00) for the second round) and intra-rater agreement was good (mKappa (95% CI) = 0.77 (0.47–1.00)). Criterion validity showed a 78 (73–84)% correctness versus gold standard. Conclusion: A preliminary primary heart involvement in systemic sclerosis consensus-based definition was created and partially validated, for use in future clinical research