Analysis of DNA ligase IV mutations found in LIG4 syndrome patients: the impact of two linked polymorphisms

LIG4 syndrome patients have hypomorphic mutations in DNA ligase IV. Although four of the five identified patients display immunodeficiency and developmental delay, one patient was developmentally normal. The developmentally normal patient had the same homozygous mutation (R278H) in DNA ligase IV as one of the more severely affected patients, who additionally had two linked polymorphisms. Here, we examine the impact of the mutations and polymorphisms identified in the LIG4 syndrome patients. Examination of recombinant mutant proteins shows that the severity of the clinical features correlates with the level of residual ligase activity. The polymorphisms decrease the activity of DNA ligase IV by approximately 2-fold. When combined with the otherwise mild R278H mutation, the activity is reduced to a level similar to other LIG4 patients who display immunodeficiency and developmental delay. This demonstrates how coupling of a mutation and polymorphism can have a marked impact on protein function and provides an example where a polymorphism may have influenced clinical outcome. Analysis of additional mutational changes in LIG4 syndrome (R580X, R814X and G469E) have led to the identification of a nuclear localization signal in DNA ligase IV and sites impacting upon DNA ligase IV adenylation.     

Are HLA-DR or TAP Genes Genetic Markers of Severity in Ulcerative Colitis?

The pathogeny of ulcerative colitis (UC) is not yet elucidated, but some arguments suggest the implication of genetic factors. Among the candidate genes, those encoding for HLA class II genotypes have been extensively studied in UC; however, discordant data may be imputable to heterogeneity, characterized by immunological markers such as atypical ANCA (p-ANCA), or to inclusion of more or less intractable UC. The aim of our study is to evaluate the interest of HLA class II and TAP genetic markers to identify different clinical forms of UC, according to p-ANCA status. Unrelated patients with a history of UC (n=91) and healthy control subjects with no personal or family history of inflammatory bowel diseases (IBD) (n=200) were included. HLA-DRB103 was less frequent in UC patients than in healthy controls (8% vs 28%,PC<0.03). No association was found with any TAP genotypes. Moreover, there was no association with the HLA-DR2 specificity, either in the entire group of UC patients (38% vs 28%) or in the p-ANCA-positive subgroup of patients (30%). The most consistent finding in the present study is that some genetic markers may characterize intractability in UC patients. HLA-DR2 was associated with poor prognosis, regardless of p-ANCA status. In HLA-DR2 and non-HLA-DR2 groups, colectomy was done in 55% and 27% of patients, respectively (PC<0.05). Furthermore, in non-HLA-DR2 patients, p-ANCA could be of interest to characterize those with more severe prognosis. Our results confirm the interest of genetic studies to define UC genetic susceptibility, taking into account intractability of the disease. They do not support the hypothesis that p-ANCA is a subclinical marker of genetic susceptibility to UC.     

Prognostic value of the Geneva prediction rule in patients with pulmonary embolism

Background

Assessment of pre-test probability of pulmonary embolism (PE) and prognostic stratification are two widely recommended steps in the management of patients with suspected PE. Some items of the Geneva prediction rule may have a prognostic value.We analyzed whether the initial probability assessed by the Geneva rule was associated with the outcome of patients with PE.

Methods

In a post-hoc analysis of a multicenter trial including 1,693 patients with suspected PE, the all-cause death or readmission rates during the 3-month follow-up of patients with confirmed PE were analyzed. PE probability group was prospectively assessed by the revised Geneva score (RGS). Similar analyses were made with the a posteriori-calculated simplified Geneva score (SGS).

Results

PE was confirmed in 357 patients and 21 (5.9%) died during the 3-month follow-up. The mortality rate differed significantly with the initial RGS group, as with the SGS group. For the RGS, the mortality increased from 0% (95% Confidence Interval: [0–5.4%]) in the low-probability group to 14.3% (95% CI: [6.3-28.2%]) in the high-probability group, and for the SGS, from 0% (95% CI: [0–5.4%] to 17.9% (95% CI: [7.4-36%]). Readmission occurred in 58 out of the 352 patients with complete information on readmission (16.5%). No significant change of readmission rate was found among the RGS or SGS groups.

Conclusions

Returning to the initial PE probability evaluation may help clinicians predict 3-month mortality in patients with confirmed PE.(ClinicalTrials.gov: NCT00117169)     

Toward a global health approach: lessons from the HIV and Ebola epidemics

Background

The imposing burden of non-communicable diseases, emerging infectious diseases, climate change, environmental consequences, migrations, urbanization, and other challenges, faced in a context that strives to make universal health coverage (UHC) a reality, compels global health professionals to ask: how do we construct a “global” roadmap that is both realistic and effective?To move forward and begin to answer this question, we draw on lessons and experiences gained during the “global” health crises triggered by the HIV and Ebola pandemics.

Main text

Improving the early response and committing to the long haul; developing inter-disciplinary and inter-sectoral responses; designing comprehensive and versatile interventions; and, most importantly, to work closely and effectively with civil society and communities are some of the critical elements that were identified.The health sector has changed dramatically in recent years; new tools and innovative technologies are transforming the culture and practice of public health. This calls for a new vision.Reprioritizing primary health care and community engagement, repositioning approaches to meet people’s needs, applying integrated disease management to respond to problems caused by the silo approach, implementing UHC, and ensuring equity are some of the new strategies.

Conclusion

These strategies must all undergo a mandatory revolution in health governance—locally and globally. It should be obvious that nothing can be improved on a global or sustainable scale without re-examining the architecture and governance of major funding and international organizations dedicated to health.Pressing economic, demographic, and climate issues related to health underscore the urgent need for these changes.

     

Bilan des enquêtes 2012, 2013 et 2014 de l’Observatoire national français des centres spécialisés de l’obésité (oNCSO)

Objective and method

The French Obesity Plan enabled the creation of 37 Specialized Obesity Centers (CSOs) in 2012 to ensure a dual mission, the multidisciplinary management of severe or complex obesity and the organization of care channels in the regions. This report takes stock of the first three years of operation of the CSOs, based on the data collected by the National Observatory of CSOs (oNCSO), set up by the General Directorate of Hospitalization and Care.