Pure varus posteromedial rotatory instability of the elbow: Radiographic findings, treatment, and outcomes.

INTRODUCTION: Although varus posteromedial rotatory instability (VPMRI) is a subtle elbow injury that involves anteromedial coronoid facet (AMCF) fracture and ligamentous injuries, treatment options and outcomes of VPMRI remains controversial. The aim of this study was to investigate radiographic findings, treatments, and outcomes of a large series of VPMRI. METHODS: We retrospectively reviewed 91 pure VPMRI cases with AMCF fracture (O'Driscoll classification anteromedial type) which were treated at 6 hospitals. Clinical and radiographic outcomes were investigated with a mean follow-up period of 46.8 months using the Mayo elbow performance score (MEPS), and the Quick Disabilities of the Arm, Shoulder and Hand (Quick-DASH) score, and serial plain radiographs. RESULTS: In AMCF fracture, there were 4 cases of subtype 1, 67 cases of subtype 2, and 20 cases of subtype 3. On MRI, complete tears of lateral collateral ligament and medial collateral ligament were observed in 83.1 % (59/71 cases) and 33.8 % (24/71 cases). Operative treatment was performed in 68 cases (74.7 %) including both side fixation in 40 cases (58.8 %), medial side fixation only in 17 cases (25.0 %), and lateral side fixation only in 11 cases (16.2 %). Nonoperative treatment was performed in 23 cases (25.3 %). The mean final MEPS and Quick-DASH scores were 93.7 and 7.9. The overall complication and reoperation rates were 22.0 % and 15.4 %. No significant differences regarding final clinical scores and range of motions were observed between the operative group and the nonoperative group, but significant differences were observed regarding number (p = 0.019) and displacement (p = 0.002) of coronoid fragment, and complication rate (p < 0.001) between the two groups. CONCLUSION: Depending on the pattern of coronoid fragment and the degree of ligamentous injuries, operative treatment of unstable VPMRI using various fixation techniques including coronoid fixation and ligament repair yielded satisfactory final clinical outcomes. However, surgeons should be aware of the high complication and reoperation rates after operative treatment. Stable VPMRI with AMCF fracture involving minimal displacement or small number of fragments can be treated nonoperatively.

miR-141/200c contributes to ethanol-mediated hepatic glycogen metabolism.

OBJECTIVE: Hepatic glucose metabolism is profoundly perturbed by excessive alcohol intake. miR-141/200c expression is significantly induced by chronic ethanol feeding. This study aimed at identifying the role of miR-141/200c in glucose homeostasis during chronic ethanol exposure. METHODS: WT and miR-141/200c KO mice were fed a control or an ethanol diet for 30 days, followed by a single binge of maltose dextrin or ethanol, respectively. Untargeted metabolomics analysis of hepatic primary metabolites was performed along with analyses for liver histology, gene expression, intracellular signaling pathways, and physiological relevance. Primary hepatocytes were used for mechanistic studies. RESULTS: miR-141/200c deficiency rewires hepatic glucose metabolism during chronic ethanol feeding, increasing the abundance of glucose intermediates including G6P, an allosteric activator for GS. miR-141/200c deficiency replenished glycogen depletion during chronic ethanol feeding accompanied by reduced GS phosphorylation in parallel with increased expression of PP1 glycogen targeting subunits. Moreover, miR-141/200c deficiency prevented ethanol-mediated increases in AMPK and CaMKK2 activity. Ethanol treatment reduced glycogen content in WT-hepatocytes, which was reversed by dorsomorphin, a selective AMPK inhibitor, while KO-hepatocytes displayed higher glycogen content than WT-hepatocytes in response to ethanol treatment. Furthermore, treatment of hepatocytes with A23187, a calcium ionophore activating CaMKK2, lowered glycogen content in WT-hepatocytes. Notably, the suppressive effect of A23187 on glycogen deposition was reversed by dorsomorphin, demonstrating that the glycogen depletion by A23187 is mediated by AMPK. KO-hepatocytes exhibited higher glycogen content than WT-hepatocytes in response to A23187. Finally, miR-141/200c deficiency led to improved glucose tolerance and insulin sensitivity during chronic ethanol feeding. CONCLUSIONS: miR-141/200c deficiency replenishes ethanol-mediated hepatic glycogen depletion through the regulation of GS activity and calcium signaling coupled with the AMPK pathway, improving glucose homeostasis and insulin sensitivity. These results underscore miR-141/200c as a potential therapeutic target for the management of alcohol intoxication.

The effects of environmental Microplastic on wharf roach (Ligia exotica): A Multi-Omics approach.

This is the first report to evaluate the potential effects of microplastics (MPs) on wild wharf roaches (Ligia exotica) in a shoreline habitant. L. exotica is an important plastic detritus consumer in coastal area. A survey was conducted from May to June in the years 2019 and 2020 in two South Korean nearshore sites: Nae-do (as MPs-uncontaminated) and Maemul-do (as MPs-contaminated). MPs (>20 µm in size) were detected highly in gastrointestinal tracts of the L. exotica from Maemul-do, at an average level of 50.56 particles/individual. They were detected in much lower levels in the L. exotica from Nae-do. at an average rate of 1.00 particles/individual. The polymer type and shape were dominated by expanded polystyrene (EPS, 93%) and fragment (99.9%) in L. exotica from Maemul-do. Especially, Hexabromocyclododecanes, brominated flame retardants added to EPS, have been detected highly in L. exotica from Maemul-do (630.86 ± 587.21 ng/g l. w.) than those of Nae-do (detection limit: 10.5 ng/g l. w). Genome-wide transcriptome profiling revealed altered expression of genes associated with fatty acid metabolic processes, the innate-immune response-activating system and vesicle cytoskeletal trafficking in L. exotica from Maemul-do. The activation of the p53 signaling pathway (which is related to proteasome, ER regulation and cell morphogenesis) is likely to be involved in the EPS-uptake of wild L. exotica. Four neurosteroids were also detected in head tissue, and cortisol and progesterone concentrations differed significantly in L. exotica from Maemul-do. Our findings also suggest that resident plastic detritus consumer might be a useful indicator organism for evaluating pollution and potential effects of environmental microplastics.

The Novel Hooked Kirschner Wire Technique for Ulna Coronoid Process Fractures.

Background: The aim of this study was to introduce a novel technique to improve the ease of fixing of even small fragments of the coronoid process and report the clinical outcomes of this method. Methods: Forty-nine patients with ulnar coronoid process fractures fixed using the hooked Kirschner wire (K-wire) technique at our hospital from 2007 to 2019 were reviewed. Radiological features and fracture union were assessed using simple radiographs. Functional outcomes of the treated elbows were evaluated at the final follow-up visit using the Mayo Elbow Performance Score (MEPS). Results: All patients were examined at a mean follow-up of 17.7 months (range, 6-62 months). We observed bony union in patients at a mean of 10.9 weeks (range, 6-22 weeks). The mean flexion and extension ranges of the elbow were 132.0° (range, 106° -151°) and 4.5° (range, -20° to 30°), respectively. The mean pronation and supination ranges of the forearm were 81.1° (range, 60°-90°) and 88.3° (range, 60°-120°), respectively. The mean arc of the elbow was 127.4° (range, 78°-160°). All patients were evaluated using the MEPS at the final follow-up visit, with a mean score of 96.9 points (range, 80-100 points). One case of coronoid nonunion was observed and re-fixation was performed. One case of infection was observed and also treated with additional surgery. Three patients complained of ulnar nerve symptoms and 1 patient underwent surgical release for tardy ulnar nerve palsy. Conclusions: Despite its limitations, the hooked K-wire technique was a useful method for even smaller coronoid process fractures. K-wires were also a useful temporary intraoperative fixation method and could provide permanent fixation.

Chemical hazard of robotic hull in-water cleaning discharge on coastal embryonic fish.

In-water cleaning (IWC) involves the removal of biofilms and foulants from the hull of a ship using brush or water jet. During IWC, several factors associated with the harmful chemical contaminants release to the marine environment, which can create "hotspots" of chemical contamination in coastal areas. To elucidate the potential toxic effects of IWC discharge, we investigated developmental toxicity in embryonic flounder, which are sensitive life stage to chemical exposure. Zinc and copper were the dominant metals, while zinc pyrithione was the most abundant biocide associated with IWC discharge in two remotely operated IWC. Discharge from IWC carried by both remotely operated vehicles (ROVs) produced developmental malformations including pericardial edema, spinal curvature, and tail-fin defects. In an analyses of differential gene expression profiles (fold-change of genes with a cutoff < 0.05) as assessed by high-throughput RNA sequencing, genes associated with muscle development were commonly and significantly changed. The gene ontology (GO) of embryos exposed to IWC discharge from ROV A activities highly enriched muscle and heart development, while cell signaling and transport were evident in embryos exposed to IWC discharge of ROV B. We analyzed the gene network by significant GO terms. In the network, TTN, MYOM1, CASP3, and CDH2 genes appeared to be key regulators of the toxic effects on muscle development. In embryos exposed to ROV B discharge, HSPG2, VEGFA, and TNF genes related to the nervous system pathway were affected. These results shed light on the potential impacts of muscle and nervous system development in non-target coastal organisms exposed to contaminants found in IWC discharge.

SerpinA3N deficiency attenuates steatosis and enhances insulin signaling in male mice.

Aberrant hepatic lipid metabolism is the major cause of non-alcoholic fatty liver disease (NAFLD) and is associated with insulin resistance and type 2 diabetes. Serine (or cysteine) peptidase inhibitor, clade A, member 3N (SerpinA3N) is highly expressed in the liver; however, its functional role in regulating NAFLD and associated metabolic disorders are not known. Male wildtype and hepatocyte Serpina3N knockout (HKO) mice were fed a control diet, methionine- and choline-deficient diet or high-fat high-sucrose diet to induce NAFLD and markers of lipid metabolism and glucose homeostasis were assessed. SerpinA3N protein was markedly induced in mice with fatty livers. Hepatic deletion of SerpinA3N attenuated steatosis which correlated with altered lipid metabolism genes, increased fatty acid oxidation activity and enhanced insulin signaling in mice with NAFLD. Additionally, SerpinA3N HKO mice had reduced epididymal white adipose tissue mass, leptin, and insulin levels, improved glucose tolerance, and enhanced insulin sensitivity which was associated with elevated insulin-like growth factor binding protein-1 (IGFBP1) and activation of the leptin receptor (LEPR)-STAT3 signaling pathway. Our findings provide a novel insight into the functional role of SerpinA3N in regulating NAFLD and glucose homeostasis.

Onepot-Seq: capturing single-cell transcriptomes simultaneously in a continuous medium via transient localization of mRNA.

The development of single-cell RNA-seq has broadened the spectrum for biological research by providing a high-resolution analysis of cellular heterogeneity. However, the requirement for sophisticated devices for the compartmentalization of cells has limited its widespread applicability. Here, we develop Onepot-Seq, a device-free method, that harnesses the transient localization of mRNA after lysis to capture single-cell transcriptomes simultaneously in a continuous fluid medium. In mixed-species experiments, we obtained high-quality single-cell profiles. Further, cell type-specific poly(A)-conjugated antibodies allow Onepot-Seq to effectively capture target cells in complex populations. Chemical perturbations to cells can be profiled by Onepot-Seq at single-cell resolution. Onepot-Seq should allow routine transcriptional profiling at single-cell resolution, accelerating clinical and scientific discoveries in many fields of science.

This article describes a strategy for single-cell RNA sequencing that avoids the usual imitation required by first physically compartmentalizing single cells. Based on the slow rate of mRNA diffusion relative to mRNA capture on beads, the authors devised a method that profiles single-cell mRNA among a multiple cell population, within one reaction mixture, termed 'Onepot-Seq'. This approach uses a time-constrained, transient reaction chamber that forms around each cell, with only slow diffusion of the cell contents after gentle lysis. The sparse distribution of cells and beads allows the beads to capture the profile of a single cell with minimal intercellular mRNA contamination.

MicroRNA-200c coordinates HNF1 homeobox B and apolipoprotein O functions to modulate lipid homeostasis in alcoholic fatty liver disease.

Hepatic steatosis is an initial manifestation of alcoholic liver disease. An imbalance of hepatic lipid processes including fatty acid uptake, esterification, oxidation, and triglyceride secretion leads to alcoholic fatty liver (AFL). However, the precise molecular mechanisms underlying the pathogenesis of AFL remain elusive. Here, we show that mice deficient in microRNAs (miRs)-141 and -200c display resistance to the development of AFL. We found that miR-200c directly targets HNF1 homeobox B (Hnf1b), a transcriptional activator for microsomal triglyceride transfer protein (Mttp), as well as apolipoprotein O (ApoO), an integral component of the mitochondrial contact site and cristae organizing system complex. We show that expression of these miRs is significantly induced by chronic ethanol exposure, which is accompanied by reduced HNF1B and APOO levels. Furthermore, miR-141/200c deficiency normalizes ethanol-mediated impairment of triglyceride secretion, which can be attributed to the restored levels of HNF1B and MTTP, as well as phosphatidylcholine abundance. Moreover, we demonstrate that miR-141/200c deficiency restores ethanol-mediated inhibition of APOO expression and mitochondrial dysfunction, improving mitochondrial antioxidant defense capacity and fatty acid oxidation. Taken together, these results suggest that miR-200c contributes to the modulation of lipid homeostasis in AFL disease by cooperatively regulating Hnf1b and ApoO functions.

Insulin Prevents Hypercholesterolemia by Suppressing 12α-Hydroxylated Bile Acids.

BACKGROUND: The risk of cardiovascular disease in type 1 diabetes remains extremely high, despite marked advances in blood glucose control and even the widespread use of cholesterol synthesis inhibitors. Thus, a deeper understanding of insulin regulation of cholesterol metabolism, and its disruption in type 1 diabetes, could reveal better treatment strategies. METHODS: To define the mechanisms by which insulin controls plasma cholesterol levels, we knocked down the insulin receptor, FoxO1, and the key bile acid synthesis enzyme, CYP8B1. We measured bile acid composition, cholesterol absorption, and plasma cholesterol. In parallel, we measured markers of cholesterol absorption and synthesis in humans with type 1 diabetes treated with ezetimibe and simvastatin in a double-blind crossover study. RESULTS: Mice with hepatic deletion of the insulin receptor showed marked increases in 12α-hydroxylated bile acids, cholesterol absorption, and plasma cholesterol. This phenotype was entirely reversed by hepatic deletion of FoxO1. FoxO1 is inhibited by insulin and required for the production of 12α-hydroxylated bile acids, which promote intestinal cholesterol absorption and suppress hepatic cholesterol synthesis. Knockdown of Cyp8b1 normalized 12α-hydroxylated bile acid levels and completely prevented hypercholesterolemia in mice with hepatic deletion of the insulin receptor (n=5-30), as well as mouse models of type 1 diabetes (n=5-22). In parallel, the cholesterol absorption inhibitor, ezetimibe, normalized cholesterol absorption and low-density lipoprotein cholesterol in patients with type 1 diabetes as well as, or better than, the cholesterol synthesis inhibitor, simvastatin (n=20). CONCLUSIONS: Insulin, by inhibiting FoxO1 in the liver, reduces 12α-hydroxylated bile acids, cholesterol absorption, and plasma cholesterol levels. Thus, type 1 diabetes leads to a unique set of derangements in cholesterol metabolism, with increased absorption rather than synthesis. These derangements are reversed by ezetimibe, but not statins, which are currently the first line of lipid-lowering treatment in type 1 diabetes. Taken together, these data suggest that a personalized approach to lipid lowering in type 1 diabetes may be more effective and highlight the need for further studies specifically in this group of patients.

Comparative toxicity study of waterborne two booster biocides (CuPT and ZnPT) on embryonic flounder (Paralichthys olivaceus).

A new generation of booster biocides that include metal pyrithiones (PTs) such as copper pyrithione (CuPT) and zinc pyrithione (ZnPT) are being used as tributyltin alternatives. In the marine environment, ZnPT can easily transchelate Cu to form CuPT, and the environmental fate and persistence of these two metal pyrithiones are closely related. Although some data on the toxicity of biocides on marine fish are available, little is known about their toxicity and toxic pathway. We thus compared the toxic effects of CuPT and ZnPT on embryonic olive flounder (Paralichthys olivaceus) by investigating their adverse effects based on developmental morphogenesis and transcriptional variation. In our study, the toxic potency of CuPT was greater with respect to developmental malformation and mortality than ZnPT. Consistent with the developmental effects, the expression of genes related to tail fin malformation (including plod2, furin, and wnt3a) was higher in embryonic flounder exposed to CuPT than in those exposed to ZnPT. Genes related to muscle and nervous system development exhibited significant changes on differential gene expression profiles using RNA sequencing (cutoff value P < 0.05). Gene ontology analysis of embryos exposed to CuPT revealed affected cellular respiration and kidney development, whereas genes associated with cell development, nervous system development and heart development showed significant variation in embryonic flounder exposed to ZnPT. Overall, our study clarifies the common and unique developmental toxic effects of CuPT and ZnPT through transcriptomic analyses in embryonic flounder.

MiR-200c-3p targets SESN1 and represses the IL-6/AKT loop to prevent cholangiocyte activation and cholestatic liver fibrosis.

Cholestasis causes ductular reaction in the liver where the reactive cholangiocytes not only proliferate but also gain a neuroendocrine-like phenotype, leading to inflammatory cell infiltration and extracellular matrix deposition and contributing to the development and progression of cholestatic liver fibrosis. This study aims to elucidate the role of miR-200c in cholestasis-induced biliary liver fibrosis and cholangiocyte activation. We found that miR-200c was extremely abundant in cholangiocytes but was reduced by cholestasis in a bile duct ligation (BDL) mouse model; miR-200c was also decreased by bile acids in vitro. Phenotypically, loss of miR-200c exacerbated cholestatic liver injury, including periductular fibrosis, intrahepatic inflammation, and biliary hyperplasia in both the BDL model and the 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) model. We identified sestrin 1 (SESN1) as a target of miR-200c. Sesn1-/--BDL mice showed mitigation of cholestatic liver injury. On a molecular level, the pro-proliferative IL-6/AKT feedback loop was activated in Mir200c-/- livers but was inhibited in Sesn1-/- livers upon cholestasis in mice. Furthermore, rescuing expression of miR-200c by the adeno-associated virus serotype 8 ameliorated BDL-induced liver injury in Mir200c-/- mice. Taken together, this study demonstrates that miR-200c restrains the proliferative and neuroendocrine-like activation of cholangiocytes by targeting SESN1 and inhibiting the IL-6/AKT feedback loop to protect against cholestatic liver fibrosis. Our findings provide mechanistic insights regarding biliary liver fibrosis, which may help to reveal novel therapeutic targets for the treatment of cholestatic liver injury and liver fibrosis.

Seawater contamination associated with in-water cleaning of ship hulls and the potential risk to the marine environment.

In-water cleaning can clear-off foulants from ship hulls to prevent transportation of non-indigenous species and reduce hull friction and consequent fuel use. However, during cleaning, antifouling paint residues containing toxic substances can be released into the environment. To understand the potential risks of in-water hull cleaning, cleaning effluents were collected and analyzed for total suspended solid (TSS), particle size distribution, and metal concentrations. TSS concentrations were 97.3-249 mg/L, corresponding to release rates of 12.9-37.5 g/m2 from the hull surface. Particles with sizes of ≥8 µm contributed 75-94% of the TSS. Average Cu and Zn concentrations in the effluents were 209 µg/L and 1510 µg/L, respectively, which were used for risk assessment in two port scenarios. Although the risks vary with the scale of the hull cleaning and the ports, in-water cleaning poses clear risks to marine environments, unless the effluents are recovered or treated before being released.

Characteristics of Elbow Dislocation in Patients with Preexisting Cubitus Varus.

BACKGROUND: The aim of this study was to investigate the clinical presentations, patterns of soft-tissue injuries, and outcomes of treatment of elbow dislocations in patients with preexisting cubitus varus. METHODS: Four cases of elbow dislocation in patients with preexisting cubitus varus, which were treated at 3 residency training hospitals, were retrospectively reviewed. Soft-tissue injury patterns were investigated using magnetic resonance imaging (MRI). Clinical outcomes were assessed at an average of 50.8 months (range, 34-82 months) after treatment using the Mayo Elbow Performance Score (MEPS) and the Quick Disabilities of the Arm, Shoulder and Hand (QuickDASH) score. RESULTS: The mean patient age was 49.5 years (range, 33-57 years). All patients had a posteromedial elbow dislocation, which was an indirect injury caused by a fall onto an outstretched hand. One patient had failed closed reduction; 3 others had redislocation or gross instability after closed reduction. Significant tears of the lateral collateral ligament complex and common extensor group were shown in MRI. All patients had surgical treatment including lateral complex repair only (n = 2), repair of both sides' complexes (n = 1), and corrective osteotomy with lateral complex repair (n = 1). At the final follow-up, the mean MEPS was 92.5 ± 8.7 and the mean QuickDASH score was 4.5 ± 6.4. CONCLUSIONS: Elbow dislocation in patients with preexisting cubitus varus may present as posteromedial dislocation with acute instability. Surgical treatment of this injury led to acceptable clinical outcomes.

Impaired host resistance to Salmonella during helminth co-infection is restored by anthelmintic treatment prior to bacterial challenge.

Intestinal helminth infection can impair host resistance to co-infection with enteric bacterial pathogens. However, it is not known whether helminth drug-clearance can restore host resistance to bacterial infection. Using a mouse helminth-Salmonella co-infection system, we show that anthelmintic treatment prior to Salmonella challenge is sufficient to restore host resistance to Salmonella. The presence of the small intestine-dwelling helminth Heligmosomoides polygyrus at the point of Salmonella infection supports the initial establishment of Salmonella in the small intestinal lumen. Interestingly, if helminth drug-clearance is delayed until Salmonella has already established in the small intestinal lumen, anthelmintic treatment does not result in complete clearance of Salmonella. This suggests that while the presence of helminths supports initial Salmonella colonization, helminths are dispensable for Salmonella persistence in the host small intestine. These data contribute to the mechanistic understanding of how an ongoing or prior helminth infection can affect pathogenic bacterial colonization and persistence in the mammalian intestine.

A Potential Role for SerpinA3N in Acetaminophen-Induced Hepatotoxicity.

Acetaminophen (APAP) is a commonly used pain and fever reliever but is also the most frequent cause of drug-induced liver injury. The mechanism pertaining acetaminophen toxicity has been well documented, whereas mechanisms of hepatotoxicity are not well established. Serine (or cysteine) peptidase inhibitor, clade A, member 3N (SerpinA3N), a serine protease inhibitor, is synthesized in the liver but the role of SerpinA3N in relation to APAP-induced liver injury is not known. Wild-type and hepatocyte-specific SerpinA3N knockout (HKO) mice were injected intraperitoneally with a single dose of PBS or APAP (400 mg/kg) for 12 hours, and markers of liver injury, cell death, and inflammation were assessed. SerpinA3N expression was highly induced in mice with APAP overdose. SerpinA3N HKO mice had diminished liver injury and necrosis as shown by lower alanine aminotransferase and interleukin-6 levels, accompanied by suppressed inflammatory cytokines and reduced neutrophil infiltration. The reduced oxidative stress was associated with enhanced antioxidant enzyme capabilities. Taken together, hepatocyte SerpinA3N deficiency reduced APAP-induced liver injury by ameliorating inflammation and modulating the 5' AMP-activated protein kinase-unc-51-like autophagy activating kinase 1 signaling pathway. Our study provides novel insights into a potential role for SerpinA3N in APAP-induced liver injury. SIGNIFICANCE STATEMENT: Our studies indicate that serine (or cysteine) peptidase inhibitor, clade A, member 3N (SerpinA3N) may have a pathophysiological role in modulating acetaminophen (APAP)-induced liver injury. More specifically, mice with hepatic deletion of SerpinA3N suppressed inflammation and liver injury to reduce APAP-induced hepatotoxicity. Controlling the inflammatory response offers possible approaches for novel therapeutics; therefore, understanding the pathophysiological role of SerpinA3N in inducing liver injury may add to the development of more efficacious treatments.

Effect of depth of anesthesia on the phase lag entropy in patients undergoing general anesthesia by propofol: A STROBE-compliant study.

The PLEM100 (Inbody Co., Ltd., Seoul, Korea) is a device for measuring phase lag entropy (PLE), a recently developed index for the quantification of consciousness during sedation and general anesthesia. In the present study, we assessed changes in PLE along with the level of consciousness during the induction of general anesthesia using propofol. PLE was compared with the bispectral index (BIS), which is currently the most commonly used index of consciousness.After obtaining Institutional Review Board approval and written informed consent, we enrolled 15 patients (8 men, 7 women; mean age: 37 ±â€Š9 years; mean height: 168 ±â€Š8 cm; mean weight; 68 ±â€Š11 kg) undergoing nasal bone reduction. PLE and BIS sensors were attached simultaneously, and general anesthesia was induced via target-controlled infusion (TCI) of propofol. PLE and BIS scores were recorded when the calculated effect site concentration shown on the TCI pump was equal to the target concentrations of 1.5, 2.0, 2.5, 2.8, 3.0, 3.2, 3.4, and 3.5 µg/mL (and at each 0.1 µg/mL increase, thereafter). Observer's Assessment of Alertness/Sedation (OAA/S) scores were also recorded until unconsciousness was achieved. Throughout the anesthesia period, all pairs of PLE and BIS data were collected using data acquisition software.The partial correlation coefficients between OAA/S scores and PLE, and between OAA/S scores and BIS were 0.778 (P < .001) and 0.846 (P < .001), respectively. Throughout the period of anesthesia, PLE and BIS exhibited a significant positive correlation. The partial correlation coefficient prior to the loss of consciousness was 0.838 (P < .001), and 0.669 (P < .001) following the loss of consciousness. Intra-class correlation between the 2 indices was 0.889 (P < .001) and 0.791 (P < .001) prior and following the loss of consciousness, respectively.PLE exhibited a strong and predictable correlation with both BIS and OAA/S scores. These results suggest that PLE is reliable for assessing the level of consciousness during sedation and general anesthesia.

Reactive metallocene cations as sensitive indicators of gas-phase oxygen and water.

Analysis of highly reactive compounds at very low concentration in solution using electrospray ionization mass spectrometry requires the use of exhaustively purified solvents. It has generally been assumed that desolvation gas purity needs to be similarly high, and so most chemists working in this space have relied upon high purity gas. However, the increasing competitiveness of nitrogen generators, which provide gas purity levels that vary inversely with flow rate, prompted an investigation of the effect of gas-phase oxygen on the speciation of ions. The most reactive species studied, the reduced titanium complex [Cp2Ti(NCMe)2]+[ZnCl3]- and the olefin polymerization pre-catalyst [Cp2Zr(µ-Me)2AlMe2]+[B(C6F5)4]-, only exhibited detectable oxidation when they were rendered coordinatively unsaturated through in-source fragmentation. Computational chemistry allowed us to find the most plausible pathways for the observed chemistry in the absence of observed intermediates. The results provide insight into the gas-phase oxidation or hydrolysis of these reactive species.

PDK4-Deficiency Reprograms Intrahepatic Glucose and Lipid Metabolism to Facilitate Liver Regeneration in Mice.

Liver regeneration requires intrahepatic and extrahepatic metabolic reprogramming to meet the high hepatic bioenergy demand for liver cell repopulation. This study aims to elucidate how pyruvate dehydrogenase kinase 4 (PDK4), a critical regulator of glucose and lipid metabolism, coordinates metabolic regulation with efficient liver growth. We found that hepatic Pdk4 expression was elevated after two-thirds partial hepatectomy (PHx). In Pdk4 -/- PHx mice, the liver/body weight ratio was more rapidly restored, accompanied by more aggressive hepatic DNA replication; however, Pdk4 -/- mice developed more severe hypoglycemia. In Pdk4 -/- PHx livers, the pro-regenerative insulin signaling was potentiated, as demonstrated by early peaking of the phosphorylation of insulin receptor, more remarkable induction of the insulin receptor substrate proteins, IRS1 and IRS2, and more striking activation of Akt. The hepatic up-regulation of CD36 contributed to the enhanced transient regeneration-associated steatosis in Pdk4 -/- PHx mice. Notably, CD36 overexpression in mice promoted the recovery of liver/body weight ratio and elevated intrahepatic adenosine triphosphate after PHx. CD36 expression was transcriptionally suppressed by FOXO1 (forkhead box protein O1), which was stabilized and translocated to the nucleus following AMPK (adenosine monophosphate-activated protein kinase) activation. PHx remarkably induced AMPK activation, which became incompetent to respond in Pdk4 -/- livers. Moreover, we defined that PDK4-regulated AMPK activation directly depended on intracellular adenosine monophosphate in vitro and in regenerative livers. Conclusion: PDK4 inhibition reprograms glucose and lipid metabolism to promote liver regeneration by enhancing hepatic insulin/Akt signaling and activating an AMPK/FOXO1/CD36 regulatory axis of lipid. These findings may lead to potential therapeutic strategies to prevent hepatic insufficiency and liver failure.

Food Craving, Seeking, and Consumption Behaviors: Conceptual Phases and Assessment Methods Used in Animal and Human Studies.

What drives us to eat? It is one of the most fundamental questions in the obesity research field which have been investigated for centuries. Numerous novel in vivo technologies in the neuroscience field allows us to reevaluate the multiple components and phases of food-related behaviors. Focused on the cognitive, executive, behavioral and temporal aspects, food-related behaviors can be distinguished into appetitive phase (food craving→food seeking) and consummatory phase (food consumption). Food craving phase is an internal state or stage in which the animal has the motivation to eat the food but there is no actual food specific behaviors or actions. Food seeking phase entails repeated behaviors with a food searching purpose until the animal discovers the food (or food-related cue) and the approach behavior stage after the discovery of food. Food consumption phase is the step that the animal grabs, chews and intake the food. This review will specifically focus on characteristics and evaluation methods for each phase of food-related behavior in rodent, non-human primates and human.

Bile Acid-Activated Receptors: A Review on FXR and Other Nuclear Receptors.

Nuclear receptors (NRs) are ligand-dependent transcription factors that are involved in various biological processes including metabolism, reproduction, and development. Upon activation by their ligands, NRs bind to their specific DNA elements, exerting their biological functions by regulating their target gene expression. Bile acids are detergent-like molecules that are synthesized in the liver. They not only function as a facilitator for the digestion of lipids and fat-soluble vitamins but also serve as signaling molecules for several nuclear receptors to regulate diverse biological processes including lipid, glucose, and energy metabolism, detoxification and drug metabolism, liver regeneration, and cancer. The nuclear receptors including farnesoid X receptor (FXR), pregnane X receptor (PXR), constitutive androstane receptor (CAR), vitamin D receptor (VDR), and small heterodimer partner (SHP) constitute an integral part of the bile acid signaling. This chapter reviews the role of the NRs in bile acid homeostasis, highlighting the regulatory functions of the NRs in lipid and glucose metabolism in addition to bile acid metabolism.