Human apolipoprotein A-I Gly26Arg stimulation of inflammatory responses via NF-kB activation: Potential roles in amyloidosis?

The cascade of molecular events leading to Human apolipoprotein A–I (apoA–I) amyloidosis is not completely understood, not even the pathways that determine clinical manifestations associated to systemic protein deposition in organs such as liver, kidney and heart. About twenty natural variants of apoA–I were described as inducing amyloidosis, but the mechanisms driving their aggregation and deposition are still unclear. We previously identified that the mutant Gly26Arg but not Lys107-0 induced the release of cytokines and reactive oxygen species from cultured RAW 264.7 murine macrophages, suggesting that part of the pathogenic pathway could elicit of an inflammatory signal. In this work we gained deep insight into this mechanism and determined that Gly26Arg induced a specific pro-inflammatory cascade involving activation of NF-κB and its translocation into the nucleus. These findings suggest that some but not all apoA–I natural variants might promote a pro-oxidant microenvironment which could in turn result in oxidative processing of the variants into a misfolded conformation.     

Identical COL71A1 heterozygous mutations resulting in different dystrophic epidermolysis bullosa phenotypes

Dystrophic epidermolysis bullosa is a rare blistering condition caused by mutations in the COL7A1 gene. Different clinical variants have been described, with dominant and recessive inheritance, but no consistent findings have been elucidated to establish a genotype–phenotype correlation. We present three unrelated patients with two identical pathogenic compound heterozygous mutations in the COL7A1 gene that developed different clinical forms of dystrophic epidermolysis bullosa—epidermolysis bullosa pruriginosa and mild recessive non‐Hallopeau–Siemens—raising the possibility of other genetic or environmental modifying factors responsible for the phenotype of the disease.     

Polymorphisms of the farnesyl diphosphate synthase gene modulate bone changes in response to atorvastatin

Although their primary therapeutic indications are different, aminobisphosphonates and statins target enzymes in the mevalonate pathway, which is critical for bone homeostasis. Previous studies have shown that some polymorphisms of the gene encoding farnesyl diphosphate synthase (FDPS), the main target of aminobisphosphonates, modulate the response to these drugs. In this study, we explored whether those single nucleotide polymorphisms (SNPs) also influence the changes in bone mineral density (BMD) following therapy with statins. Sixty-six patients with coronary heart disease were studied at baseline and after 1-year therapy with atorvastatin. BMD was measured by DXA. Three SNPs of the FDPS gene (rs2297480, rs11264359 and rs17367421) were analyzed by using Taqman assays. The results showed that there was no association between the SNPs and basal BMD. However, rs2297480 and rs11264359 alleles, which are in linkage disequilibrium, were associated with changes in hip BMD following atorvastatin therapy. Thus, patients with AA genotype at the rs2297480 locus had a 0.8 ± 0.8 % increase in BMD at the femoral neck, whereas in patients with AC/CC genotypes, BMD showed a 2.3 ± 0.8 % decrease (p = 0.02). Similar results were obtained regarding changes of BMD at the femoral trochanter and when alleles at the rs11264359 locus were analyzed. However, there was no association between BMD and rs17367421 alleles. In conclusion, these results suggest that polymorphisms of the FDPS gene may influence the bone response to various drugs targeting the mevalonate pathway, including not only aminobisphosphonates but also statins.     

COVID-19 Pandemic: The Role of EMS Physicians in a Community Response Effort

Abstract

The COVID-19 pandemic is a worldwide historical event that will continue to affect nearly every aspect of ordinary life, including affecting our economic, political, and healthcare eco-systems. An effective pandemic response demands a coordinated and integrated response across community healthcare stakeholders, including Public Health and Emergency Management Officials. EMS systems are in a unique position and perform an essential role on the frontlines of COVID-19, including facilitating coordination of response efforts to COVID-19 within their communities while supporting public health mitigation efforts to slow the spread of the SARS-CoV-2. EMS physicians serve their communities at a unique intersection as clinical leaders, population health experts, and advocates. This paper examines and recommends crucial roles for EMS physician leaders as communities work together in pandemic response.