Context: The impairment of insulin sensitivity, a marker of surgical stress, is important for outcomes.
Objective: The aim was to assess the association between the quality of preoperative glycemic ...control, intraoperative insulin sensitivity, and adverse events after cardiac surgery.
Design and Setting: We conducted a prospective cohort study at a tertiary care hospital.
Subjects: Nondiabetic and diabetic patients scheduled for elective cardiac surgery were included in the study. Based on their glycosylated hemoglobin A (HbA1c), diabetic patients were allocated to a group with good (HbA1c <6.5%) or poor (HbA1c >6.5%) glycemic control.
Intervention: We used the hyperinsulinemic-normoglycemic clamp technique.
Main Outcome Measures: The primary outcome was insulin sensitivity measurement. Secondary outcomes were major complications within 30 d after surgery including mortality, myocardial failure, stroke, dialysis, and severe infection (severe sepsis, pneumonia, deep sternal wound infection). Other outcomes included minor infections, blood product transfusions, and the length of intensive care unit and hospital stay.
Results: A total of 143 nondiabetic and 130 diabetic patients were studied. In diabetic patients, a negative correlation (r = −0.527; P < 0.001) was observed between HbA1c and intraoperative insulin sensitivity. Diabetic patients with poor glycemic control had a greater incidence of major complications (P = 0.010) and minor infections (P = 0.006). They received more blood products and spent more time in the intensive care unit (P = 0.030) and the hospital (P < 0.001) than nondiabetic patients. For each 1 mg · kg−1 · min−1 decrease in insulin sensitivity, the incidence of major complications increased (P = 0.004).
Conclusions: In diabetic patients, HbA1c levels predict insulin sensitivity during surgery and possibly outcome. Intraoperative insulin resistance is associated with an increased risk of complications, independent of the patient’s diabetic state.
In diabetic patients, HbA1c levels predict intraoperative insulin sensitivity during cardiac surgery and are possibly associated with an increased risk of complications.
Background & Aims Esophageal squamous cell carcinoma (ESCC) is the predominant form of esophageal cancer in Japan. Smoking and drinking alcohol are environmental risk factors for ESCC, whereas single ...nucleotide polymorphisms in ADH1B and ALDH2 , which increase harmful intermediates produced by drinking alcohol, are genetic risk factors. We conducted a large-scale genomic analysis of ESCCs from patients in Japan to determine the mutational landscape of this cancer. Methods We performed whole-exome sequence analysis of tumor and nontumor esophageal tissues collected from 144 patients with ESCC who underwent surgery at 5 hospitals in Japan. We also performed single-nucleotide polymorphism array-based copy number profile and germline genotype analyses of polymorphisms in ADH1B and ALDH2 . Polymorphisms in CYP2A6, which increase harmful effects of smoking, were analyzed. Functions of TET2 mutants were evaluated in KYSE410 and HEK293FT cells. Results A high proportion of mutations in the 144 tumor samples were C to T substitution in CpG dinucleotides (called the CpG signature) and C to G/T substitutions with a flanking 5′ thymine (called the APOBEC signature). Based on mutational signatures, patients were assigned to 3 groups, which associated with environmental (drinking and smoking) and genetic (polymorphisms in ALDH2 and CYP2A6 ) factors. Many tumors contained mutations in genes that regulate the cell cycle ( TP53, CCND1, CDKN2A , FBXW7 ); epigenetic processes ( MLL2, EP300, CREBBP , TET2 ); and the NOTCH ( NOTCH1 , NOTCH3 ), WNT ( FAT1 , YAP1 , AJUBA ) and receptor-tyrosine kinase−phosphoinositide 3-kinase signaling pathways ( PIK3CA , EGFR , ERBB2 ). Mutations in EP300 and TET2 correlated with shorter survival times, and mutations in ZNF750 associated with an increased number of mutations of the APOBEC signature. Expression of mutant forms of TET2 did not increase cellular levels of 5-hydroxymethylcytosine in HEK293FT cells, whereas knockdown of TET2 increased the invasive activity of KYSE410 ESCC cells. Computational analyses associated the mutations in NFE2L2 we identified with transcriptional activation of its target genes. Conclusions We associated environmental and genetic factors with base substitution patterns of somatic mutations and provide a registry of genes and pathways that are disrupted in ESCCs. These findings might be used to design specific treatments for patients with esophageal squamous cancers.
Adrenoleukodystrophy (ALD) is an X-linked disease that affects primarily the white matter of the central nervous system and adrenal cortex. A correlation between genotypes and phenotypes has not been ...observed. Here, we present two Japanese siblings with a novel missense variant (c.1887T > G) in the ABCD1 gene who presented with different clinical phenotypes, i.e., adolescent cerebral and cerebello-brainstem types. We also review the literature focusing on the variation in the clinical phenotypes within ALD families. In our review, 61.9% of sibling pairs presented with the same clinical type of ALD and 59.1% of sibling pairs presented with a similar age of onset. Conversely, 15.4% of sibling pairs had a similar age of onset, but different clinical types of ALD. To observe the correlation between genotypes and phenotypes, it is important to diagnose early and to accumulate reports describing age of onset, first onset symptom, and progression of the symptom.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Multiple system atrophy (MSA) is a rare, late-onset, and devastating neurodegenerative disease characterized by autonomic failure, alongside with various combination of parkinsonism, cerebellar ...ataxia, and pyramidal dysfunction. Since we first identified biallelic mutations in the COQ2 gene in two multiplex MSA families and further reported that heterozygous COQ2 V393A variant confers a susceptibility to sporadic MSA, the results of nearly a decade of investigating this association globally were quite remarkable. COQ2 V393A was virtually absent in the American and European populations but was shown to have varying associations with sporadic MSA in the East Asian populations. In our attempt to clarify the latter and provide a coherent regional conclusion, we conducted two independent case-control series which showed clear association of the V393A variant with sporadic MSA in the Japanese population. We then pooled the results with other studies from the East Asian population and conducted a meta-analysis which broadened and established the association regionally (pooled OR 2.12, 95% CI: 1.35–3.31, PI: 0.63–7.15, p = 0.0047). The subgroup analysis identified a strong association of V393A with MSA-C (pooled OR 2.57, 95% CI: 1.98–3.35; p = 2.56 × 10−12) but not with MSA-P (pooled OR 1.41, 95% CI: 0.88–2.26; p = 0.16). Our results highlighted the importance of investigating region-specific and pan-regional genetic variants that may potentially underlie the pathomechanisms of neurodegenerative diseases. COQ2 V393A variant remains a susceptibility variant rather than causative for MSA particularly, MSA-C subtype, in the East Asian population.
•Association of COQ2 V393A variant with MSA in East Asian populations.•COQ2 V393A carrier frequencies underlie variable associations with MSA globally.•COQ2 V393A is specifically associated with the MSA-C subtype.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Hf0.5Zr0.5O2 thin films are not always ferroelectric. This work investigates the impact of annealing temperature and time on the crystalline structures and dielectric properties of 10 nm thick ...Hf0.5Zr0.5O2 thin films. It is found that the tetragonal phase crystal is formed from the amorphous film firstly, then transforms to the orthorhombic and monoclinic phases, in accordance with the annealing temperature and time. The volume fraction of the orthorhombic phase in the film, which is known as the origin of ferroelectricity, becomes dominant in a certain range of the annealing condition. Thus, the annealing temperature and time are responsible for the anti-ferroelectric, ferroelectric, and paraelectric characteristics of Hf0.5Zr0.5O2 thin films. This phase transformation behavior is discussed from the viewpoint of formation energies of the respective crystal phases, which accompanies the changes of unit cell volumes. The competition of transformation rates between the tetragonal to orthorhombic and the orthorhombic to monoclinic is key for the formation of ferroelectric films.
Postoperative pain and inflammation are significant complications following surgery. Strategies that aim to prevent excessive inflammation without hampering natural wound-healing are required for the ...management of postoperative pain and inflammation. However, the knowledge of the mechanisms and target pathways involved in these processes is lacking. Recent studies have revealed that autophagy in macrophages sequesters pro-inflammatory mediators, and it is therefore being recognized as a crucial process involved in regulating inflammation. In this study, we tested the hypothesis that autophagy in macrophages plays protective roles against postoperative pain and inflammation and investigated the underlying mechanisms.
Postoperative pain was induced by plantar incision under isoflurane anesthesia in mice lacking macrophage autophagy (Atg5flox/flox LysMCre +) and their control littermates (Atg5flox/flox). Mechanical and thermal pain sensitivity, changes in weight distribution, spontaneous locomotor activity, tissue inflammation, and body weight were assessed at baseline and 1, 3, and 7 days after surgery. Monocyte/macrophage infiltration at the surgical site and inflammatory mediator expression levels were evaluated.
Atg5flox/flox LysMCre + mice compared with the control mice exhibited lower mechanical and thermal pain thresholds and surgical/non-surgical hindlimb weight-bearing ratios. The augmented neurobehavioral symptoms observed in the Atg5flox/flox LysMCre + mice were associated with more severe paw inflammation, higher pro-inflammatory mediator mRNA expression, and more monocytes/macrophages at the surgical site.
The lack of macrophage autophagy augmented postoperative pain and inflammation, which were accompanied by enhanced pro-inflammatory cytokine secretion and surgical-site monocyte/macrophage infiltration. Macrophage autophagy plays a protective role in postoperative pain and inflammation and can be a novel therapeutic target.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Ultrashort-channel junctionless FETs (JL-FETs) were fabricated on silicon-on-insulator substrates utilizing atomically sharp V-shaped grooves produced by anisotropic wet etching. The channel length, ...defined as the width of the V-groove bottom, was as short as 3 nm, and the channel thickness was between 1 and 8 nm. Excellent transistor characteristics with threshold voltages that are optimal for low-power operation were obtained for both n-FETs and p-FETs when the thickness of both the channel and gate dielectric film thickness was reduced to 1 nm. The origin of the excellent electrostatic control is discussed on the basis of fringe capacitance and quantum confinement effects in a nanometer-scale ultrathin Si layer where band-gap expansion, dielectric constant reduction, and increase in the dopant activation energy become prominent. The electrical characteristics of the ultrashort channel JL-FETs were found to be very sensitive to device parameters such as the channel thickness and dopant concentration.
Sodium ion transportation plays a crucial role in the pathogenesis of hypoxic-ischemic brain injury. Amiodarone, a Vaughan-Williams class III antiarrhythmic drug, has been widely used to treat ...life-threatening arrhythmia and cardiac arrest worldwide. In addition to its inhibitory effects on the potassium channel, amiodarone also blocks various sodium ion transporters, including the voltage-gated sodium channel, sodium pump, and Na
/Ca
exchanger. Considering these pharmacological profile, amiodarone may affect the influx-efflux balance of sodium ion in the hypoxic-ischemic brain. Previous studies suggest that the blockade of the voltage-gated sodium channel during hypoxic-ischemic brain injury exerts neuroprotection. On the contrary, the blockade of sodium pump or Na
/Ca
exchanger during hypoxia-ischemia may cause further intracellular sodium accumulation and consequent osmotic cell death. From these perspectives, the effects of amiodarone on sodium ion balance on the hypoxic-ischemic brain can be both protective and detrimental depending on the clinical and pathophysiological conditions. In this study, we therefore investigated the effect of amiodarone on hypoxic-ischemic brain injury using a murine experimental model.
Compared with the control group mice, mice that received amiodarone after induction of 40-min hypoxic-ischemic brain injury exhibited lower survival rates over 7 days and worse neurological function. After 25-min hypoxic-ischemic brain injury, amiodarone treated mice exhibited larger infarct volumes (16.0 ± 6.9 vs. 24.2 ± 6.8 mm
, P < 0.05) and worse neurological function. In addition, the brains harvested from the amiodarone-treated mice contained larger amounts of sodium (194.7 ± 45.1 vs. 253.5 ± 50.9 mEq/kg dry weight, P < 0.01) and water (259.3 ± 8.9 vs. 277.2 ± 12.5 mg, P < 0.01). There were no significant differences in hemodynamic parameters between groups.
Amiodarone exacerbated brain injuries and neurological outcomes after hypoxic-ischemic insults. Severe brain sodium accumulation and brain edema were associated with the detrimental effects of amiodarone. Amiodarone at the clinical dose can exacerbate brain injury after hypoxic-ischemic insult by affecting sodium ion transportation and facilitate intracellular sodium accumulation in the brain.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Loss-of-function (LoF) variants in NEK1 have recently been reported to be associated with amyotrophic lateral sclerosis (ALS). In this study, we investigated the association of NEK1 LoF variants with ...an increased risk of sporadic ALS (SALS) and the clinical characteristics of patients with SALS carrying LoF variants in a Japanese case series. Whole-exome sequencing analysis was performed for a series of 446 SALS patients in whom pathogenic variants in familial ALS-causative genes have not been identified and 1163 healthy control subjects in our Japanese series. We evaluated LoF variants, defined as nonsense, splice-site disrupting single-nucleotide variants (SNVs), or short insertion/deletion (indel) variants predicted to cause frameshifts in NEK1. We identified seven NEK1 LoF variants in patients with SALS (1.57%), whereas only one was identified in control subjects (0.086%) (P = 0.00073, Fisher's exact test). This finding is consistent with those in recent reports from other regions in the world. In conclusion, we demonstrated that NEK1 LoF variants are also associated with an increased risk of SALS in the Japanese population.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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