Alzheimer's disease (AD) is a slowly progressive form of dementia, characterized by memory impairment and cognitive dysfunction. AD is mainly characterized by the deposition of amyloid β (Aβ) plaques and intracellular neurofibrillary tangles in the brain, along with neuronal degeneration and high levels of oxidative stress. Cilostazol (CSZ) was recently found to suppress the progression of cognitive decline in patients with stable AD receiving acetylcholinesterase inhibitors. This present study aimed to clarify the mechanism by which CSZ protects neurons from degeneration associated with Aβ(1-42). We used Aβ(1-42) to induce neurotoxicity in human neuroblastoma SH-SY5Y cells. Cells were pretreated with CSZ before co-treatment with Aβ. To evaluate the effect of CSZ on oxidative stress, we examined levels of reactive oxygen species (ROS), nicotinamide adenine dinucleotide phosphate oxidase (Nox) activity, mRNA expression of NOX4, and Cu/Zn-Superoxide Dismutase (SOD), as well as apoptosis biomarkers [MTT, (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide), caspase-3 and -9 activities and staining of annexin V]. We also assayed the activity of mitogen-activated protein kinases (MAPK): p38 MAPK and extracellular signal-regulated kinase1/2 (ERK1/2), and biomarkers of mitochondrial function (Bcl-2 and Bax), and cyclic adenosine monophosphate response element-binding protein (CREB). Aβ-induced oxidative stress (ROS, NOX4 activity, and expression of NOX mRNA), caspase activation (caspase-3 and -9), and p38 MAPK phosphorylation were suppressed by co-treatment with CSZ, but not by ERK1/2 activation. In addition, pretreatment with CSZ suppressed Aβ-induced apoptosis and increased cell viability via suppression of Bax (a proapoptotic protein), upregulation of Bcl-2 (an antiapoptotic protein) and Cu/Zn-SOD (a superoxide scavenging enzyme), and phosphorylation of CREB.Abbreviations: Aβ, amyloid β; AD, Alzheimer's disease; AMPK, AMP-activated protein kinase; APP, β-amyloid precursor protein; ASK, apoptosis signal-regulating kinase; ATRA, all-trans-retinoic acid; CREB, cyclic adenosine monophosphate response element-binding protein; CSZ, cilostazol; DTT, dithiothreitol; EDTA, ethylenediaminetetraacetic acid; ERK, extracellular signal-regulated kinase; FBS, Fetal bovine serum; HRP, Horseradish Peroxidase; JNK, c-jun N-terminal kinase; MAPK, mitogen-activated protein kinases; MCI, mild cognitive impairment; MEK, MAPK/ERK kinase; MKK, mitogen activated kinase kinase; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; NADPH, nicotinamide adenine dinucleotide phosphate; NOX, nicotinamide adenine dinucleotide phosphate oxidase; PBS, phosphate-buffered saline; PCR, polymerase chain reaction; PDE, phosphodiesterase; RLU, relative light units; ROS, reactive oxygen species; SOD, Superoxide dismutase; TMB, 3,3 ,5,5 -tetramethylbenzidine. These findings suggested that CSZ could counteract neurotoxicity through multiple mechanisms, one mechanism involving the attenuation of oxidative stress by suppressing NOX activ...

A 23-year-old healthy man was scheduled for extraction of his mandibular third molars under general anesthesia with nasotracheal intubation. Sudden sinus tachycardia up to 170 beats/min occurred when applying an epinephrine solution-soaked swab into the nasal cavity for preventing epistaxis during intubation. This was presumably evoked by submucosal migration of the swab into a false passage created because of the force applied during a prior failed attempt at nasal passage of the tracheal tube, and rapid epinephrine absorption by the traumatized mucosa. The causes of the unexpected severe tachycardia in our patient are discussed.

: Silencing of gene expression by RNA interference RNAi has become a widely used tool for assessing gene function in a fast and easy manner. An important advance in the RNAi eld was the discovery that plasmid-based short hairpin RNA transcription can substitute for synthetic small interference RNAs both in vitro and in vivo. The constitutive knockdown of gene expression by RNAi can limit the scope of experiments, especially if the inhibition of genes leads to cell lethality, which prevents in vivo functional analysis. We have generated double-conditional short hairpin RNA from a single vector that can regulate its own transcription by a combination of tetracycline-inducible and Cre-loxP systems. This vector will be useful for the control of short hairpin RNA expression in a spatially-regulated manner by Cre recombinase as well as a temporally-regulated manner by tetracycline induction. These control features provide for the speci c silencing of genes to facilitate functional genetic analysis in mammals in vivo.

Background The telemedicine intensive care unit (Tele-ICU) is defined as a system in which intensive care professionals remotely provide care to critically ill patients and support the on-site staff in the intensive care unit (ICU) using secured audio–video and electronic links. Although the Tele-ICU is expected to resolve the shortage of intensivists and reduce the regional disparities in intensive care resources, the efficacy has not yet been evaluated in Japan because of a lack of clinically available system. Methods This was a single-center, historical comparison study in which the impact of the Tele-ICU on ICU performance and changes in workload of the on-site staff were evaluated. The Tele-ICU system developed in the United States was used. Data for 893 adult ICU patients before the Tele-ICU implementation and for all adult patients registered in the Tele-ICU system from April 2018 to March 2020 were abstracted and included. We investigated ICU and hospital mortality and length of stay and ventilation duration after the Tele-ICU implementation in each ICU, and compared between pre and post implementation and changes over time. We also assessed physician workload as defined by the frequency and duration of access to the electronic medical record (EMR) of the targeted ICU patients. Results After the Tele-ICU implementation 5438 patients were included. In unadjusted data pre/post study showed significant decreases in ICU (8.5–3.8%) and hospital (12.4–7.7%) mortality and ICU length of stay (p < 0.001), and those values were maintained for 2 years. In data stratified by predicted hospital mortality, ICU and hospital actual mortality in high and medium risk patients decreased significantly after the implementation. Ventilation duration was shortened (p < 0.007). Access frequency of the on-site physicians decreased by 25%, and the decrease occurred in the daytime shift and in the physicians with 3–15 years of work experience. Conclusions Our study showed the Tele-ICU implementation was associated with lower mortality, especially in medium and high risk patients, and decreased EMR-related tasks of on-site physicians. These results suggest that the Tele-ICU could be a solution of the shortage of intensivists and regional disparities for intensive care.

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