RESUMO
BACKGROUND: People with diabetes mellitus (DM) have increased infection risk. The healthcare utilization of pediatric and adolescent diabetic patients with infection is not well defined. This study evaluates the number of pediatric and adolescent patients with DM that seek medical treatment for infection management and assesses its socioeconomic impact. METHODS: A retrospective analysis was performed using the Pediatric Health Information System (PHIS) database on children and adolescents with DM who presented to the Emergency Department (ED) or were hospitalized for infection management from 2008 to 2014. The PHIS database collects admission, demographic, and economic data from 44 freestanding children's hospitals across the United States. RESULTS: In total, 123 599 diabetic patient encounters were identified (77% type 1 DM, 23% type 2 DM). ED visits and hospitalizations for type 1 DM and type 2 DM increased throughout the study period. Total charges for these encounters were greater than $250 million dollars per year and increased each year. Infection encounters make up more than 30% of that cost while accounting for only 14% of the visits. Respiratory infections were the most common type of infection followed by skin and soft tissue infections for both ED care and inpatient hospitalizations. Patients with infections had longer hospital length of stay and higher cost per day than those without infections. CONCLUSIONS: Children and adolescents with type 1 and type 2 DM commonly present to the ED and require hospitalization for infection evaluation and management. Encounters with infection make up a large proportion of a growing economic burden on the United States' healthcare system. As the prevalence of DM grows, this burden can be expected to become even more significant. Cost-effective strategies for the prevention of infection in pediatric patients with DM are needed.
Assuntos
Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 2/complicações , Serviço Hospitalar de Emergência/estatística & dados numéricos , Hospitalização/estatística & dados numéricos , Infecções/etiologia , Adolescente , Criança , Feminino , Preços Hospitalares/estatística & dados numéricos , Hospitalização/economia , Hospitais Pediátricos/economia , Hospitais Pediátricos/estatística & dados numéricos , Humanos , Infecções/economia , Infecções/epidemiologia , Masculino , Estudos Retrospectivos , Estados Unidos/epidemiologiaRESUMO
The mechanics of hMSH2-hMSH6 ATP binding and hydrolysis are critical to several proposed mechanisms for mismatch repair (MMR), which in turn rely on the detailed coordination of ATP processing between the individual hMSH2 and hMSH6 subunits. Here we show that hMSH2-hMSH6 is strictly controlled by hMSH2 and magnesium in a complex with ADP (hMSH2(magnesium-ADP)-hMSH6). Destabilization of magnesium results in ADP release from hMSH2 that allows high affinity ATP binding by hMSH6, which then enhances ATP binding by hMSH2. Both subunits must be ATP-bound to efficiently form a stable hMSH2-hMSH6 hydrolysis-independent sliding clamp required for MMR. In the presence of magnesium, the ATP-bound sliding clamps remain on the DNA for â¼8 min. These results suggest a precise stepwise kinetic mechanism for hMSH2-hMSH6 functions that appears to mimic G protein switches, severely constrains models for MMR, and may partially explain the MSH2 allele frequency in Lynch syndrome or hereditary nonpolyposis colorectal cancer.
Assuntos
Trifosfato de Adenosina/química , Proteínas de Ligação a DNA/química , Complexos Multienzimáticos/química , Proteína 2 Homóloga a MutS/química , Difosfato de Adenosina/química , Difosfato de Adenosina/genética , Difosfato de Adenosina/metabolismo , Trifosfato de Adenosina/genética , Trifosfato de Adenosina/metabolismo , Neoplasias Colorretais Hereditárias sem Polipose/enzimologia , Neoplasias Colorretais Hereditárias sem Polipose/genética , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Humanos , Hidrólise , Cinética , Complexos Multienzimáticos/genética , Complexos Multienzimáticos/metabolismo , Proteína 2 Homóloga a MutS/genética , Proteína 2 Homóloga a MutS/metabolismoRESUMO
DNA nucleotide mismatches and lesions arise on chromosomes that are a complex assortment of protein and DNA (chromatin). The fundamental unit of chromatin is a nucleosome that contains approximately 146 bp DNA wrapped around an H2A, H2B, H3, and H4 histone octamer. We demonstrate that the mismatch recognition heterodimer hMSH2-hMSH6 disassembles a nucleosome. Disassembly requires a mismatch that provokes the formation of hMSH2-hMSH6 hydrolysis-independent sliding clamps, which translocate along the DNA to the nucleosome. The rate of disassembly is enhanced by actual or mimicked acetylation of histone H3 within the nucleosome entry-exit and dyad axis that occurs during replication and repair in vivo and reduces DNA-octamer affinity in vitro. Our results support a passive mechanism for chromatin remodeling whereby hMSH2-hMSH6 sliding clamps trap localized fluctuations in nucleosome positioning and/or wrapping that ultimately leads to disassembly, and highlight unanticipated strengths of the Molecular Switch Model for mismatch repair (MMR).
