Presenilins (PS1 and PS2) are multi-functional proteins involved in a diverse array of molecular and cellular functions, including proteolysis, development, neurogenesis, synaptic plasticity, ion channel regulation and phospholipid metabolism. Mutations in presenilin genes are responsible for the majority of Familial Alzheimer disease (FAD). Consequently, FAD-associated mutations in genes encoding PS1 or PS2 lead to several key cellular phenotypes, including alterations in proteolysis of β-amyloid precursor protein (APP) and Ca2+ entry. The mechanism underlying presenilin (PS)-mediated modulation of Ca2+ entry remains to be determined. Our previous studies showed that the PS-dependent down-regulation of phosphatidylinositol-4,5-bisphosphate (PIP2) is attributable to the observed Ca2+ deficits. In this study, we attempted to identify the ion channel that is subject to the PIP2 and PS-dependent modulation. We found that Ca2+ or Zn2+ entry via the transient receptor potential melastatin 7 (TRPM7) channel was attenuated by the presence of FAD-associated PS1 mutants, such as ΔE9 and L286V. TRPM7 has been implicated in Mg2+ homeostasis and embryonic development. The intracellular delivery of PIP2 restored TRPM7-mediated Ca2+ influx, indicating that the observed deficits in Ca2+ entry are due to down-regulation of PIP2. Conversely, PS1 and PS2 deficiency, previously shown to up-regulate PIP2 levels, potentiated TRPM7-mediated Ca2+ influx. PS-dependent changes in Ca2+ influx could be neutralized by a TRPM7 channel blocker. Collectively, these results indicate that TRPM7 may underlie the Ca2+ entry deficits observed in FAD-associated PS mutants and suggest that the normal function of PS involves regulation of TRPM7 through a PIP2-dependent mechanism.
These results suggest that elderly patients aged 80-85 years with advanced gastric cancer could expect a better prognosis with surgical resection. However, extreme-elderly patients aged ≥86 years should consider the risks and benefits of surgical treatment.
Background/AimsIntranasal mupirocin and chlorhexidine bathing are candidate strategies to prevent healthcare-associated infections caused by methicillin-resistant Staphylococcus aureus (MRSA). In Korea, intranasal mupirocin is not available, and mupirocin ointment, an over-the-counter drug, has been used indiscriminately. Furthermore, because it is covered by health insurance, mupirocin is easy to prescribe within hospitals.MethodsWe performed a mupirocin drug utilization review (DUR) within Hallym University Sacred Heart Hospital. Annual use of mupirocin was investigated between 2003 and 2013, and monthly consumption of mupirocin was assessed during the final 2-year period. The DUR focused on August 2012, the period of highest use of mupirocin. Also, we investigated trends in mupirocin resistance in MRSA between 2011 and 2013.ResultsAnnual consumption of mupirocin increased from 3,529 tubes in 2003 to 6,475 tubes in 2013. During August 2012, 817 tubes were prescribed to 598 patients; of these, 84.9% were prescribed to outpatients, and 77.6% at the dermatology department. The most common indication was prevention of skin infections (84.9%), and the ointment was combined with systemic antibiotics in 62.9% of cases. The average duration of systemic antibiotic administration was about 7.8 days. The rate of low-level mupirocin resistance in MRSA increased from 8.0% to 22.0%, and that of high-level mupirocin resistance increased from about 4.0% to about 7.5%.ConclusionsInappropriate use of mupirocin is prevalent. Considering the increase in resistance and the future application of intranasal mupirocin, prophylactic use of mupirocin in dermatology departments should be reconsidered.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.