Context:
Acrodysostosis is a rare skeletal dysplasia that is associated with multiple resistance to G protein-coupled receptor (GPCR) signaling hormones in a subset of patients. Acrodysostosis is ...genetically heterogeneous because it results from heterozygous mutations in PRKAR1A or PDE4D, two key actors in the GPCR-cAMP-protein kinase A pathway.
Objective:
Our objective was to identify the phenotypic features that distinguish the two genotypes causing acrodysostosis.
Patients and Methods:
Sixteen unrelated patients with acrodysostosis underwent a candidate-gene approach and were investigated for phenotypic features.
Results:
All patients had heterozygous de novo mutations. Fourteen patients carried a PRKAR1A mutation (PRKAR1A patients), five each a novel PRKAR1A mutation (p.Q285R, p.G289E, p.A328V, p.R335L, or p.Q372X), nine the reported PRKAR1A p.R368X mutation; two patients harbored a mutation in PDE4D (PDE4D patients) (one novel mutation, p.A227S; one reported, p.E590A). All PRKAR1A, but none of the PDE4D mutated patients were resistant to PTH and TSH. Two PRKAR1A patients each with a novel mutation presented a specific pattern of brachydactyly. One PDE4D patient presented with acroskyphodysplasia. Additional phenotypic differences included mental retardation in PDE4D patients. In addition, we report the presence of pigmented skin lesions in PRKAR1A and PDE4D patients, a feature not yet described in the acrodysostosis entity.
Conclusions:
All PRKAR1A and PDE4D patients present similar bone dysplasia characterizing acrodysostosis. Phenotypic differences, including the presence of resistance to GPCR-cAMP signaling hormones in PRKAR1A but not PDE4D patients, indicate phenotype-genotype correlations and highlight the specific contributions of PRKAR1A and PDE4D in cAMP signaling in different tissues.
Abstract Background X-linked hypophosphatemia (XLH) is a rare inherited phosphate-wasting disorder associated with bone and dental complications. Health-related quality of life (HRQoL) is reduced in ...XLH patients on conventional treatment with phosphate supplements and active vitamin D, while information on patients treated with burosumab is rare. Methods HRQoL was assessed in 63 pediatric XLH patients participating in a prospective, observational study and patient registry in Germany using the KIDSCREEN-52 survey instrument and standardized qualitative interviews. Results The median age of the XLH patients was 13.2 years (interquartile range 10.6 – 14.6). At the time of the survey, 55 (87%) patients received burosumab and 8 (13%) conventional treatment. Forty-six patients (84%) currently being treated with burosumab previously received conventional treatment. Overall, HRQoL was average compared to German reference values (mean ± SD: self-report, 53.36 ± 6.47; caregivers’ proxy, 51.33 ± 7.15) and even slightly above average in some dimensions, including physical, mental, and social well-being. In general, XLH patients rated their own HRQoL higher than their caregivers. In qualitative interviews, patients and caregivers reported that, compared with conventional therapy, treatment with burosumab reduced stress, bone pain, and fatigue, improved physical health, and increased social acceptance by peers and the school environment. Conclusions In this real-world study in pediatric XLH patients, HRQoL was average or even slightly above that of the general population, likely due to the fact that the vast majority of patients had their treatment modality switched from conventional treatment to burosumab resulting in improved physical health and well-being. Graphical abstract
Group practices are increasingly common for primary care physicians worldwide. Although breakups are likely to happen frequently within group practices, their process has not been studied to date. ...The aims of this study were therefore to explore the reasons for breakups of group practices of general practitioners and to describe the associated feelings.
We conducted a qualitative study consisting of in-depth interviews of 21 general practitioners and one secretary from past group practices in the Rhône-Alpes region, France, who experienced a breakup.
When getting started in group practice for the first time, young doctors did not feel ready and supported, and did not necessarily share the same expectations as their partners. The reasons for the breakups involved imbalances within the groups, contrasting working and management styles, and breakdowns in communication. The breakup process often generated long-persistent feelings of suffering and failure for almost every partner who experienced a breakup, particularly for the partner who was leaving.
Weakening factors exist from the very beginning of a partnership, and problems are likely to increase at every change or event occurring in the group. We provide several recommendations, including fair management, a shared project based on a precise contract, the consultation of third parties as necessary and, in the worst case scenario, leaving the group practice in time.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Group practices are increasingly common for primary care physicians worldwide. Although breakups are likely to happen frequently within group practices, their process has not been studied to date. ...The aims of this study were therefore to explore the reasons for breakups of group practices of general practitioners and to describe the associated feelings.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Provider: - Institution: - Data provided by Europeana Collections- Transatlantic differences over the future of the Iran nuclear deal - or the Joint Comprehensive Plan of Action (JCPOA) of July 2015 ...- are damaging a nuclear accord that all parties, except the United States, see as delivering on its purpose. They also increase the risk of Washington and European capitals working at cross-purposes vis-à-vis Iran and broader regional policies. To avoid such a scenario, the E3 (France, Germany, United Kingdom)/European Union (EU) and the United States need to set up new channels of communication to avoid a transatlantic rift, to attempt - if at all possible - to preserve the Iran deal, and to secure its benefits for regional and global security. (author's abstract)- All metadata published by Europeana are available free of restriction under the Creative Commons CC0 1.0 Universal Public Domain Dedication. However, Europeana requests that you actively acknowledge and give attribution to all metadata sources including Europeana
The neoplastic cells of CLL are able to produce TNF which is known to stimulate the proliferation of CLL cells in an autocrine and paracrine manner. Genetic polymorphism of molecules of the TNF ...ligand superfamily has been described and certain alleles were suspected to predispose to variant biological responses. Previously, the rare allele TNFB*1 of the TNF‐β/lymphotoxin (LT)‐α gene (NcoI, asparagine at amino acid position 26) was found to be associated with a stronger LT‐α response of PBMC in vitro.
We now report on a significant increase of the allele TNF1 (TNFA −308 G) of the TNF‐α promoter/enhancer polymorphism in a group of 73 CLL patients when compared to healthy individuals (RR=3.18, 95% confidence interval 1.57–8.3; P=0.006). The allelic distribution of the TNF‐β/LT‐α NcoI polymorphism did not differ significantly from randomized healthy controls. On the other hand, the frequency of the allele TNFB*2 was increased in CLL patients with advanced clinical stage (P=0.0004). These findings indicate immunogenetic associations involving polymorphisms of cytokine genes serving as paracrine and autocrine growth factors, which thus can contribute to the pathogenesis of the TNF/LT‐sensitive haematological malignancy CLL.
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