These findings challenge in some ways previous work and

These findings challenge in some ways previous work and underpin alternative hypotheses to link insulin resistance and NP deficiency. One first possibility is that NP deficiency requires additional factors than insulin resistance only. This may include hyperglycemia and low-grade inflammation. This hypothesis is supported by a number of studies showing an elevated p-Cresyl sulfate of NPRC at the mRNA and protein level in adipose tissue and skeletal muscle of obese individuals with T2D lean with normal glucose tolerance (). A chronic increase in adipose NPRC expression could trigger a down-regulation of circulating NP levels on the long-term. This is consistent with studies in mouse models of obesity and T2D (db/db mice) where NPRC protein content is up-regulated in fat and muscle tissue and negatively correlates with circulating NP levels (). Another alternative is that NP deficiency occurs at the tissue level before circulating levels are impacted. This also implies that NP deficiency precedes insulin resistance and T2D. This is in line with previous studies demonstrating a down-regulation of NPRA mRNA and protein level in fat tissue and skeletal muscle in obesity and T2D both in humans and mice (). This is also consistent with prospective studies showing that low circulating levels of NP are predictive of new onset T2D ().
Pulmonary embolism is caused by blockage of an artery in the lung due to a clot that travels from elsewhere in the body. The main causes are stasis, surgery and cancer, but older age, use of oral contraceptives, and prior unprovoked venous thromboembolism in non-anticoagulated patients are also clear risk factors for pulmonary embolism (). When pulmonary embolism causes sudden death and common risk factors are not identified in young decedents, thrombophilia tests are requested, but only factor V Leiden and prothrombin G20210A are sequenced. However, they play little role in fatal pulmonary embolism (). Thrombophilia is an abnormality of blood coagulation that increases the risk of thrombosis (). It may be congenital or acquired. Congenital thrombophilia may be caused by an excess activity of coagulation factors or by the inefficient inhibition of certain coagulation factors by natural anticoagulants. The main causes of congenital thrombophilia are Factor V Leiden and Prothrombin G20210A, although they provoke mild risk of thrombosis (). However, deficiencies of natural anticoagulants (antithrombin, Protein C, and Protein S) significantly increase the risk of thrombosis with an estimated risk of thrombosis of up to 50-fold for the antithrombin deficiency (). The work of Halvorsen and coworkers argues the requirement of a thrombophilia study that includes the assay of anticoagulants antithrombin, protein C, and protein S in those decedents beyond idiopathic fatal pulmonary embolism. They also study other genes related to thrombophilia in these samples, but they only find association with mutations in natural anticoagulants (). This thrombophilia study is justified since the anti-coagulant deficiencies are hereditary disorders. Knowledge of the anticoagulant-deficiency justifies the thrombophilia study of the family members and may help physicians in the management of certain situations with high risk of thrombosis such as pregnancy, birth control, or any surgery. The anticoagulant function of antithrombin, protein C, and protein S may be easily evaluated by functional tests. Unfortunately, biochemical-based blood testing for natural anticoagulants is not feasible in postmortem samples and the only tool available is the gene testing. After well-defined selection criteria, the cohort in which Halvorsen and coworkers perform whole exome sequencing (WES) with collapsing analysis for cases controls is small, but allows the identification of 13.2% cases with severe thrombophilia due to natural anticoagulant deficiency. This result completely supports the sequencing of , and genes in cases of idiopathic fatal pulmonary embolism.