Risk factors for postoperative nausea and vomiting after video-assisted thoracic surgery esophagectomy: a prospective cohort study.

Video-assisted thoracic surgery esophagectomy (VATS-E) may increase the risk of postoperative nausea and vomiting (PONV) because it uses a high dosage of anesthesia through a long operative duration. However, no study has examined the risk factors for PONV after VATS-E. Therefore, we investigated the risk factors for PONV to support the appropriate risk management of PONV after VATS-E. This prospective cohort study included 155 patients who underwent VATS-E at the Showa University Hospital between April 1st, 2020 and November 30th, 2022. The primary outcome was the incidence of PONV within 24 h after surgery. Significant independent risk factors associated with the incidence of PONV were selected using multivariate analysis. The association between the number of risk factors for PONV and incidence of PONV was analyzed. One-hundred fifty-three patients were included in the analysis. The patients' median age was 67 years (range, 44-88), and 79.1% were male. PONV occurred in 35 (22.9%) patients. In the multivariate analysis, remifentanil dosage > 89.0 ng/kg/ min, albumin ≤ 3.5 g/dL, and eGFR < 60 mL/min/1.73 m 2 were independent significant risk factors for PONV. A significant association was observed between the incidence of and the number of risk factors for PONV (0 factor, 5.8%; 1 factor, 27.3%; ≥ 2 factors, 40.0%; p = 0.001). These three risk factors are useful indicators for selecting patients at high risk of developing PONV after VATS-E. In these patients, avoiding the development of PONV will be possible by performing appropriate risk management.

The Piccolo Intronic Single Nucleotide Polymorphism rs13438494 Regulates Dopamine and Serotonin Uptake and Shows Associations with Dependence-Like Behavior in Genomic Association Study.

Piccolo (PCLO) inhibits methamphetamine-induced neuropharmacological effects via modulation of dopamine (DA) uptake and regulation of the transport of synaptic vesicles in neuronal cells. Clinical studies have recently suggested that the single nucleotide polymorphism (SNP) rs13438494 in the intron 24 of the PCLO gene is associated with psychiatric disorder, in the meta-analysis of GWAS. Therefore, in this study, we attempted to evaluate the possible role of the PCLO SNP in the mechanisms of uptake of monoamines. To characterize rs13438494 in the PCLO gene, we constructed plasmids carrying either the C or A allele of the SNP and transiently transfected them into SH-SY5Y cells to analyze genetic effects on the splicing of PCLO mRNA. The C and A allele constructs produced different composition of the transcripts, indicating that the intronic SNP does affect the splicing pattern. We also transfected DA and serotonin (5-hydroxytryptamine; 5- HT) transporters into cells and analyzed their uptakes to elucidate the association to psychiatric disorders. In the cells transfected with the C allele, both the DA and 5-HT uptake were enhanced compared to the A allele. We also conducted a clinical study, in order to clarify the genetic associations. PCLO rs13438494 exhibits a relationship with the symptoms of drug dependence or related parameters, such as the age of first exposure to methamphetamine, eating disorders, tobacco dependence and fentanyl requirement. Our findings suggest that rs13438494 is associated with drug abuse and contributes to the pathogenesis of psychiatric disorders via modulation of neurotransmitter turnover.

Permanent acceptance of mouse cardiac allografts with CD40 siRNA to induce regulatory myeloid cells by use of a novel polysaccharide siRNA delivery system.

The CD40/CD154 co-stimulatory pathway is crucial in alloimmune response. We developed a novel small interfering RNA (siRNA) delivery system with a poly-dA extension at the 5'-end of the siRNA sense strand that was stably incorporated into 1,3-ß-glucan (schizophyllan, SPG). This was captured and incorporated into dendritic cells (DCs) through its receptor, Dectin-1, specifically silencing CD40 genes (siCD40) to exert immunoregulatory activity. siCD40/SPG-treated CBA mice permanently accepted B10 fully mismatched cardiac allografts. Consistent with graft survival, the infiltration of CD4(+), CD8(+) T cells into the graft was lower, and that the numbers of CD40(low)CD11c(+) DCs cells and CD4(+)Foxp3(+)cells were increased in both the graft and in the recipient spleen. In addition, naive CBA recipients given an adoptive transfer of splenocytes from the primary recipients with siCD40/SPG accepted a heart graft from donor-type B10, but not third-party Balb/c mice. In conclusion, the treatment with siCD40/SPG targeting DCs could generate antigen-specific Tregs, resulting in the permanent acceptance of mouse cardiac allografts. These findings have important implications for clarifying the mechanism underlying the induction of tolerance in DCs, and also highlight the potential of immunomodulation and the feasibility of siRNA-based clinical therapy in the transplantation field.

Three-dimensional reconstruction of rat knee joint using episcopic fluorescence image capture.

OBJECTIVE: Development of the knee joint was morphologically investigated, and the process of cavitation was analyzed by using episcopic fluorescence image capture (EFIC) to create spatial and temporal three-dimensional (3D) reconstructions. METHODS: Knee joints of Wister rat embryos between embryonic day (E)14 and E20 were investigated. Samples were sectioned and visualized using an EFIC. Then, two-dimensional image stacks were reconstructed using OsiriX software, and 3D reconstructions were generated using Amira software. RESULTS: Cavitations of the knee joint were constructed from five divided portions. Cavity formation initiated at multiple sites at E17; among them, the femoropatellar cavity (FPC) was the first. Cavitations of the medial side preceded those of the lateral side. Each cavity connected at E20 when cavitations around the anterior cruciate ligament (ACL) and posterior cruciate ligament (PCL) were completed. CONCLUSION: Cavity formation initiated from six portions. In each portion, development proceeded asymmetrically. These results concerning anatomical development of the knee joint using EFIC contribute to a better understanding of the structural feature of the knee joint.

Improved electronic coupling in hybrid organic-inorganic nanocomposites employing thiol-functionalized P3HT and bismuth sulfide nanocrystals.

In this study, we employ a thiol-functionalized polymer (P3HT-SH) as a leverage to tailor the nanomorphology and electronic coupling in polymer-nanocrystal composites for hybrid solar cells. The presence of the thiol functional group allows for a highly crystalline semiconducting polymer film at low thiol content and allows for improved nanomorphologies in hybrid organic-inorganic systems when employing non-toxic bismuth sulfide nanocrystals. The exciton dissociation efficiency and carrier dynamics at this hybrid heterojunction are investigated through photoluminescence quenching and transient absorption spectroscopy measurements, revealing a larger degree of polaron formation when P3HT-SH is employed, suggesting an increased electronic interaction between the metal chalcogenide nanocrystals and the thiol-functionalized P3HT. The fabricated photovoltaic devices show 15% higher power conversion efficiencies as a result of the improved nanomorphology and better charge transfer mechanism together with the higher open circuit voltages arising from the deeper energy levels of P3HT-SH.

Genome-wide association study identifies a potent locus associated with human opioid sensitivity.

Opioids, such as morphine and fentanyl, are widely used as effective analgesics for the treatment of acute and chronic pain. In addition, the opioid system has a key role in the rewarding effects of morphine, ethanol, cocaine and various other drugs. Although opioid sensitivity is well known to vary widely among individual subjects, several candidate genetic polymorphisms reported so far are not sufficient for fully understanding the wide range of interindividual differences in human opioid sensitivity. By conducting a multistage genome-wide association study (GWAS) in healthy subjects, we found that genetic polymorphisms within a linkage disequilibrium block that spans 2q33.3-2q34 were strongly associated with the requirements for postoperative opioid analgesics after painful cosmetic surgery. The C allele of the best candidate single-nucleotide polymorphism (SNP), rs2952768, was associated with more analgesic requirements, and consistent results were obtained in patients who underwent abdominal surgery. In addition, carriers of the C allele in this SNP exhibited less vulnerability to severe drug dependence in patients with methamphetamine dependence, alcohol dependence, and eating disorders and a lower 'Reward Dependence' score on a personality questionnaire in healthy subjects. Furthermore, the C/C genotype of this SNP was significantly associated with the elevated expression of a neighboring gene, CREB1. These results show that SNPs in this locus are the most potent genetic factors associated with human opioid sensitivity known to date, affecting both the efficacy of opioid analgesics and liability to severe substance dependence. Our findings provide valuable information for the personalized treatment of pain and drug dependence.

Imitation and observational learning of hand actions: prefrontal involvement and connectivity.

The first aim of this event-related fMRI study was to identify the neural circuits involved in imitation learning. We used a rapid imitation task where participants directly imitated pictures of guitar chords. The results provide clear evidence for the involvement of dorsolateral prefrontal cortex, as well as the fronto-parietal mirror circuit (FPMC) during action imitation when the requirements for working memory are low. Connectivity analyses further indicated a robust connectivity between left prefrontal cortex and the components of the FPMC bilaterally. We conclude that a mechanism of automatic perception-action matching alone is insufficient to account for imitation learning. Rather, the motor representation of an observed, complex action, as provided by the FPMC, only serves as the 'raw material' for higher-order supervisory and monitoring operations associated with the prefrontal cortex. The second aim of this study was to assess whether these neural circuits are also recruited during observational practice (OP, without motor execution), or only during physical practice (PP). Whereas prefrontal cortex was not consistently activated in action observation across all participants, prefrontal activation intensities did predict the behavioural practice effects, thus indicating a crucial role of prefrontal cortex also in OP. In addition, whilst OP and PP produced similar activation intensities in the FPMC when assessed during action observation, during imitative execution, the practice-related activation decreases were significantly more pronounced for PP than for OP. This dissociation indicates a lack of execution-related resources in observationally practised actions. More specifically, we found neural efficiency effects in the right motor cingulate-basal ganglia circuit and the FPMC that were only observed after PP but not after OP. Finally, we confirmed that practice generally induced activation decreases in the FPMC during both action observation and imitation sessions and outline a framework explaining the discrepant findings in the literature.

Population pharmacokinetic analysis of meropenem in Japanese adult patients.

WHAT IS KNOWN AND OBJECTIVE: Meropenem is frequently employed as an empirical treatment for serious infections, but there has been no report on its population pharmacokinetic parameters for Japanese patients. Our aim is to undertake a population pharmacokinetic analysis of meropenem using non-linear mixed effects model (NONMEM). METHODS: Data from 68 patients were analysed via NONMEM with the first-order method. The participants' covariates, including gender, age, actual body weight, serum creatinine, serum albumin, serum total protein and creatinine clearance, were analyzed by the forward inclusion and backward elimination method to identify their potential influence on meropenem pharmacokinetics. The adequacy of the constructed model was assessed by goodness-of-fit plots and the precision of the parameter estimated at each step of the model development. To assess the robustness of the estimated parameter, bootstrap analysis was performed. RESULTS AND DISCUSSION: The data were best described by a one-compartment model. The serum creatinine values modified by the below normal limit in our hospital (mSCR) were an influential covariate for clearance (CL): CL (L/h) = 11·1 × (mSCR/0·7)(-1). The volume of distribution was estimated as 33·6 L. The coefficient of variation of the inter-individual variability of CL and the residual variability were 52·1% and 0·827% µg/mL, respectively. A comparison of the population pharmacokinetic parameters of meropenem in the final model estimated in NONMEM with original data, and 1000 bootstrap samples shows that both sets of estimates were comparable, thereby indicating the robustness of the proposed model. WHAT IS NEW AND CONCLUSION: A population pharmacokinetic model that satisfactorily described the disposition and variability of meropenem in our Japanese population is described. NONMEM analysis showed that the clearance of meropenem depended on modified serum creatinine. The results of this study should help Japanese patients on meropenem by improving the prediction accuracy of dosing using the Bayesian method.

Prevalence of intestinal parasites and genotyping of Giardia intestinalis in pet shop puppies in east Japan.

The current study examined the prevalence of intestinal parasites and genotypes of Giardia intestinalis in puppies from nine pet shops in east Japan. Fresh fecal samples from 1794 puppies (≦3 months old) were collected on one occasion. Giardia spp. was examined for specific coproantigen using ELISA kit (SNAP®Giardia, IDEXX Laboratories, Inc., USA). Other intestinal parasites were detected microscopically using the formalin-ethyl acetate sedimentation technique. Genotyping was determined for the random 29 stool samples identified as Giardia spp. positive using PCR and direct sequencing of the glutamate dehydrogenase (gdh) gene. Overall prevalence of protozoan Giardia spp. and Cystoisospora spp. revealed 23.4% and 11.3%, respectively. Prevalence of ascarids, Strongyloides spp. and hookworms were recorded 1.8%, 1.1% and 0.1%, respectively. Protozoan Giardia spp. and Cystoisospora spp., thus, represent important pathogens among pet shop puppies. All genotyped G. intestinalis isolates were belonged to assemblage C or D, identified as dog-specific genotypes. Zoonotic assemblage A and B were not demonstrated. The result suggests that the risk of zoonotic transmission of G. intestinalis from pet shops puppies to humans may be quite low in Japan.

A nonsynonymous polymorphism in cannabinoid CB2 receptor gene is associated with eating disorders in humans and food intake is modified in mice by its ligands.

Marijuana use activates cannabinoid receptors (CB-Rs) producing several behavioral effects related to addiction, mood, and appetite. We investigated the association between CNR2 gene, which encodes cannabinoid CB2 receptor (CB2-R) and eating disorders in 204 subjects with eating disorders and 1876 healthy volunteers in Japanese population. The effect of treatment with CB2-R ligands on mouse food consumption was also determined. The CB2-R ligands used suppressed food intake in a time- and strain-dependent manner when food was available ad libitum and during the 12-h fast except, AM 630-the CB2-R antagonist that stimulated food consumption in food-deprived mice. There is an association between the R63Q polymorphism of the CNR2 gene and eating disorders (P = 0.04; Odds ratio 1.24, 95% CI, (1.01-1.53). These results suggest that cannabinoid CB2-R is involved in the endocannabinoid signaling mechanisms associated with the regulation of food intake and in eating disorders.

Evaluation of NT-pro BNP and CT-ANP as markers of concentric hypertrophy in dogs with a model of compensated aortic stenosis.

BACKGROUND: Serum C-terminal atrial natriuretic peptide (CT-ANP) and N-terminal pro B-type natriuretic peptide (NT-pro BNP) concentrations have not been measured serially in dogs with chronic pressure overload of the heart. HYPOTHESIS: We investigated whether serial evaluation of CT-ANP and NT-pro BNP concentrations is a useful guide to the risk of cardiac remodeling in dogs with a model of aortic stenosis. ANIMALS: Six male Beagles. METHODS: After anesthesia, the aorta was constricted with a polyester band and mean left ventricular systolic pressure (LVPs) was 50 mmHg above baseline. Echocardiographic and intracardiac catheter examinations and blood sampling were performed before surgery and 3 and 6 months after surgery. RESULTS: LVP and left ventricular end-diastolic pressure (LVEDP) were significantly higher at 6 months. Compared with baseline, end-diastolic intraventricular septum thickness (IVSd), left ventricular posterior wall thickness (LVPWd), and relative wall thickness (RWT) were significantly increased 3 and 6 months after aortic constriction. Serum CT-ANP concentrations were increased significantly at 3 months and serum NT-pro BNP concentrations were significantly higher 3 and 6 months after aortic constriction. Serum NT-pro BNP concentration was significantly correlated with LVEDP and IVSd whereas serum CT-ANP concentration was not correlated with any measurement. Stepwise regression analysis showed that LVEDP, IVSd, and RWT could predict serum NT-pro BNP. CONCLUSIONS AND CLINICAL IMPORTANCE: This study indicated the differential regulation of NT-pro BNP and CT-ANP concentrations during pressure overload. NT-pro BNP assay may be used as an additional screening method to stratify early-stage ventricular remodeling because of aortic constriction.

Secretory PLA2 inhibitor indoxam suppresses LDL modification and associated inflammatory responses in TNFalpha-stimulated human endothelial cells.

BACKGROUND AND PURPOSE: Secretory phospholipase A2 (sPLA2) is implicated in atherosclerosis, although the effects of specific sPLA2 inhibitors have not been studied. We investigated the effects of the indole analogue indoxam on low-density lipoprotein (LDL) modification by sPLA2 enzymes of different types and on the associated inflammatory responses in human umbilical vein endothelial cells (HUVEC). EXPERIMENTAL APPROACH: LDL modification was assessed by measuring the contents of two major molecular species of lysophosphatidylcholine (LPC) using electrospray ionization-liquid chromatography/mass spectrometry. The proinflammatory activity of the modified LDL was evaluated by determining monocyte chemoattractant protein-1 (MCP-1) mRNA expression and transcriptional factor nuclear factor-kappaB (NF-kappaB) activity in HUVEC. KEY RESULTS: Indoxam dose-dependently inhibited palmitoyl- and stearoyl-LPC production in LDL incubated with snake venom sPLA2 (IC50 1.2 microM for palmitoyl-LPC, 0.8 microM for stearoyl-LPC). MCP-1 mRNA expression and NF-kappaB activity were enhanced by venom sPLA2-treated LDL, which was completely suppressed by indoxam but not by thioetheramide-PC, a competitive sPLA2 inhibitor. Indoxam also suppressed LPC production in LDL treated with human synovial type IIA sPLA2. Tumour necrosis factor alpha (TNFalpha) increased type V sPLA2 expression in HUVEC. Indoxam dose-dependently suppressed LPC production in native and glycoxidized LDL treated with TNFalpha-stimulated HUVEC. Indoxam suppressed MCP-1 mRNA expression and NF-kappaB activity in TNFalpha-stimulated HUVEC incubated with native or glycoxidized LDL. CONCLUSIONS AND IMPLICATIONS: Indoxam prevented sPLA2-induced LPC production in native and glycoxidized LDL as well as LDL-induced inflammatory activity in HUVEC. Our results suggest that indoxam may be a potentially useful anti-atherogenic agent.

Evaluation of plasma C-terminal atrial natriuretic peptide in healthy cats and cats with heart disease.

BACKGROUND: The clinical implications of evaluating C-terminal atrial natriuretic peptide (ANP) concentration in cats are still controversial. HYPOTHESIS: The objective of this study was to investigate the relationship between plasma C-terminal ANP concentration and left atrial pressure (LAP) in healthy cats with volume overload (study 1), and to compare plasma C-terminal ANP in normal cats and cats with cardiomyopathy (study 2). ANIMALS: Five healthy adult cats were used in study 1, and clinically healthy cats (n=8) and cats with cardiomyopathy (n=14) were used in study 2. METHODS: In study 1, cats were anesthetized and given acetated Ringer's solution (100 mL/kg/h for 60 minute) via the cephalic vein. Hemodynamic measurements and blood samples, collected from the jugular vein, were performed at 10-min intervals. In study 2, blood samples from normal cats and cats with cardiomyopathy were collected from the cephalic vein. The plasma C-terminal ANP concentration was determined by radioimmunoassay for human alpha-ANP. RESULTS: In study 1, volume overload significantly increased the C-terminal ANP concentration and LAP from baseline. The C-terminal ANP concentration was strongly correlated with the mean LAP. In study 2, age, E wave velocity, and the ratios of the left atrium to aorta were significantly higher in the cats with cardiomyopathy compared with the normal cats. The C-terminal ANP concentration was significantly higher in the cats with cardiomyopathy compared with the normal cats. CONCLUSIONS AND CLINICAL IMPORTANCE: Our results suggest that the measurement of plasma C-terminal ANP in cats may provide additional information for the diagnosis of heart disease.

Pharmacogenetic characterization of sulfasalazine disposition based on NAT2 and ABCG2 (BCRP) gene polymorphisms in humans.

The role of breast cancer resistance protein (BCRP), an efflux ABC transporter, in the pharmacokinetics of substrate drugs in humans is unknown. We investigated the impact of genetic polymorphisms of ABCG2 (421C>A) and NAT2 on the pharmacokinetics of sulfasalazine (SASP), a dual substrate, in 37 healthy volunteers, taking 2,000 mg of conventional SASP tablets. In ABCG2, SASP AUC(0-48) of C/C, C/A, and A/A subjects was 171 +/- 85, 330 +/- 194, and 592 +/- 275 microg h/ml, respectively, with significant differences among groups. In contrast, AUC(0-48) of sulfapyridine (SP) tended to be lower in subjects with the ABCG2-A allele as homozygosity. In NAT2, AUC(AcSP)/AUC(SP) was significantly higher in rapid than in intermediate and slow acetylator (SA) genotypes. We successfully described the pharmacokinetics of SASP, SP, and N -acetylsulfapyridine (AcSP) simultaneously by nonlinear mixed-effects modeling (NONMEM) analysis with regard to both gene polymorphisms. The data indicate that SASP is a candidate probe of BCRP, particularly in its role in intestinal absorption.

SLCO1B1 (OATP1B1, an uptake transporter) and ABCG2 (BCRP, an efflux transporter) variant alleles and pharmacokinetics of pitavastatin in healthy volunteers.

To investigate the contribution of genetic polymorphisms of SLCO1B1 and ABCG2 to the pharmacokinetics of a dual substrate, pitavastatin, 2 mg of pitavastatin was administered to 38 healthy volunteers and pharmacokinetic parameters were compared among the following groups: 421C/C(*)1b/(*)1b (group 1), 421C/C(*)1b/(*)15 (group 2), 421C/C(*)15/(*)15 and 421C/A(*)15/(*)15 (group 3), 421C/A(*)1b/(*)1b (group 4), 421A/A(*)1b/(*)1b (group 5), and 421C/A(*)1b/(*)15 (group 6). In SLCO1B1, pitavastatin area under plasma concentration-time curve from 0 to 24 h (AUC(0-24)) for groups 1, 2, and 3 was 81.1+/-18.1, 144+/-32, and 250+/-57 ng h/ml, respectively, with significant differences among all three groups. In contrast to SLCO1B1, AUC(0-24) in groups 1, 4, and 5 was 81.1+/-18.1, 96.7+/-35.4, and 78.2+/-8.2 ng h/ml, respectively. Although the SLCO1B1 polymorphism was found to have a significant effect on the pharmacokinetics of pitavastatin, a nonsynonymous ABCG2 variant, 421C>A, did not appear to be associated with the altered pharmacokinetics of pitavastatin.

Involvement of cannabinoid CB2 receptor in alcohol preference in mice and alcoholism in humans.

We tested if cannabinoid type 2 receptor (CB2) in the central nervous system plays a role in alcohol abuse/dependence in animal model and then examined an association between the CB2 gene polymorphism and alcoholism in human. Mice experiencing more alcohol preference by drinking showed reduced Cb2 gene expression, whereas mice with little preference showed no changes of it in ventral midbrain. Alcohol preference in conjunction with chronic mild stress were enhanced in mice treated with CB2 agonist JWH015 when subjected to chronic stress, whereas antagonist AM630 prevented development of alcohol preference. There is an association between the Q63R polymorphism of the CB2 gene and alcoholism in a Japanese population (P=0.007; odds ratio 1.25, 95% CI, (1.06-1.47)). CB2 under such environment is associated with the physiologic effects of alcohol and CB2 antagonists may have potential as therapies for alcoholism.