Synthesis of novel triplet drugs with 1,3,5-trioxazatriquinane skeletons and their pharmacologies. 1: Synthesis of triplet drugs with morphinan skeletons

We synthesized symmetrical and nonsymmetrical triplet drugs with 1,3,5-trioxazatriquinane skeletons. The isolation of key intermediates, oxazoline dimers, made it possible to effectively produce nonsymmetrical triplets. Among the synthesized triplets, KNT-93, composed of three identical opioid μ receptor agonists, showed dose-dependent antinociception via the μ receptor. The effect was 56-fold more potent than that of morphine, a representative μ agonist. The profound analgesic effect induced by KNT-93 might result from simultaneous occupation of three μ opioid receptors.     

Interleukin-6 as an independent predictor of future cardiovascular events in high-risk Japanese patients: comparison with C-reactive protein

Inflammation is associated with the development of atherosclerotic vascular lesions and some inflammatory parameters are used as cardiovascular (CV) risk markers. The present study was designed to assess the predictive power of interleukin (IL)-6 for future CV events. In 121 Japanese patients with multiple CV risk factors and/or disease, serum concentrations of IL-6 and high sensitive C-reactive protein (hs-CRP) were measured. During follow-up periods (mean, 2.9 years) after the baseline assessment, 50 patients newly experienced CV events such as stroke/transient ischemic attack (n=10), heart failure hospitalization (n=6), acute coronary syndrome (n=7), and revascularization for coronary artery disease (n=15) and peripheral arterial disease (n=12). The serum level of IL-6, but not hs-CRP, was significantly higher in patients who had CV events than in event-free subjects (3.9±2.6 and 3.0±2.2 pg/mL, P=0.04). When the patients were divided into three groups by tertiles of basal levels of IL-6 (<1.85, 1.85-3.77, and ≥3.77 pg/mL), cumulative event-free rates by the Kaplan-Meier method were decreased according to the increase in basal IL-6 levels (65%, 50%, and 19% in the lowest, middle, and highest tertiles of IL-6, respectively; log-rank test, P=0.002). By univariate Cox regression analysis, previous CV disease, creatinine clearance, and serum IL-6 levels were significantly associated with CV events during follow-up. Among these possible predictors, the highest tertile of IL-6 was only an independent determinant for the morbidity in the multivariate analysis (hazard ratio 2.80 vs. lowest tertile, P=0.006). These findings indicate that IL-6 is a powerful independent predictor of future CV events in high-risk Japanese patients, suggesting its predictive value is superior to that of hs-CRP.     

KF-1 Ubiquitin Ligase: Anxiety Suppressor Model

Anxiety disorders are the most popular psychiatric disease in any human societies irrespective of nation, culture, religion, economics or politics. Anxiety expression mediated by the amygdala may be suppressed by signals transmitted from the prefrontal cortex and hippocampus. KF-1 is an endoplasmic reticulum (ER)-based E3-ubiquitin (Ub) ligase with a RING-H2 finger motif at the C-terminus. The kf-1 gene expression is up-regulated in the frontal cortex and hippocampus in rats after anti-depressant treatments. The kf-1 null mice show no apparent abnormalities, but exhibit selectively pronounced anxiety-like behaviors or increased timidity-like responses. The kf-1 orthologous genes had been generated after the Poriferan emergence, and are found widely in all animals except insects, arachnids and threadworms such as Drosophila, Ixodes and Caenorhabditis, respectively. This suggests that the kf-1 gene may be relevant to some biological functions characteristic to animals. Based on these observations, the Anxiety Suppressor Model has been proposed, which assumes that KF-1 Ub ligase may suppress the amygdala-mediated anxiety by degrading some anxiety promoting protein(s), such as a neurotransmitter receptor, through the ER-associated degradation pathway in the frontal cortex and hippocampus. According to this model, the emotional sensitivity to environmental stresses may be regulated by the cellular protein level of KF-1 relative to that of the putative anxiety promoter. The kf-1 null mice should be useful in elucidating the molecular mechanisms of the anxiety regulation and for screening novel anxiolytic compounds, which may block the putative anxiety promoter.     

Seroprevalence of Toxoplasma gondii in wild boars (Sus scrofa leucomystax) and wild sika deer (Cervus nippon) in Gunma Prefecture, Japan

The ingestion of undercooked meat from wild animals can be a source of Toxoplasma gondii infection in humans and other animals. In this study, we determined the seroprevalence of T. gondii infection in 175 wild boars (Sus scrofa leucomystax) and 107 wild sika deer (Cervus nippon) hunted in 2004–2007 in Gunma Prefecture, Japan, by using a commercial latex agglutination test (LAT). Antibodies (LAT, 1:64 or higher) to T. gondii were found in 6.3% of wild boars and 1.9% of sika deer. This is the first record of T. gondii infection in wild deer in Japan, and deer and wild boar meat should be cooked well before human consumption.     

Dysregulation of IFN system can lead to poor response to pegylated interferon and ribavirin therapy in chronic hepatitis C

Background

Despite being expensive, the standard combination of pegylated interferon (Peg-IFN)- α and ribavirin used to treat chronic hepatitis C (CH) results in a moderate clearance rate and a plethora of side effects. This makes it necessary to predict patient outcome so as to improve the accuracy of treatment. Although the antiviral mechanism of genetically altered IL28B is unknown, IL28B polymorphism is considered a good predictor of IFN combination treatment outcome.

Methodology

Using microarray, we quantified the expression profile of 237 IFN related genes in 87 CH liver biopsy specimens to clarify the relationship between IFN pathway and viral elimination, and to predict patients'' clinical outcome. In 72 out of 87 patients we also analyzed IL28B polymorphism (rs8099917).

Principal Findings

Five IFN related-genes (IFI27, IFI 44, ISG15, MX1, and OAS1) had expression levels significantly higher in nonresponders (NR) than in normal liver (NL) and sustained virological responders (SVR); this high expression was also frequently seen in cases with the minor (TG or GG) IL28B genotype. The expression pattern of 31 IFN related-genes also differed significantly between NR and NL. We predicted drug response in NR with 86.1% accuracy by diagonal linear discriminant analysis (DLDA).

Conclusion

IFN system dysregulation before treatment was associated with poor IFN therapy response. Determining IFN related-gene expression pattern based on patients'' response to combination therapy, allowed us to predict drug response with high accuracy. This method can be applied to establishing novel antiviral therapies and strategies for patients using a more individual approach.     

Different Impacts of Neck Circumference and Visceral Obesity on the Severity of Obstructive Sleep Apnea Syndrome

Our aim was to investigate the significance of neck circumference (NC) on the presence and severity of obstructive sleep apnea (OSA) syndrome independent of visceral fat (VF) obesity. A total of 219 subjects with suspected OSA underwent a complete polysomnography (PSG) study, along with the measurement of NC, and total body fat (TF) and VF levels (VFLs) measured by bioelectrical impedance analysis. We proposed NC divided by height (NC/H) as the simple index for height‐corrected NC in Japanese subjects. NC/H exhibited a significantly stronger correlation than NC per se with BMI (r = 0.781 vs. 0.675, P = 0.0178), TF (r = 0.531 vs. 0.156, P < 0.0001), and VF (r = 0.819 vs. 0.731, P = 0.0203), indicating that NC/H is a better indicator of visceral obesity than NC per se. Interestingly, despite the strong correlation between NC/H and VFL, VFL was significantly associated with the apnea‐hypopnea index (AHI) ≥5, ≥15, and ≥30, but not with ≥40 or ≥50, whereas NC/H was significantly associated with higher AHI values, i.e., AHI ≥50 but not with lower AHI value. Furthermore, multiple regression analyses revealed that VFL and NC/H were independently associated with the square root of AHI (AHI^0.5) levels in obese and nonobese patients, respectively. In conclusion, NC is associated with the severity of OSA independently of visceral obesity, especially in nonobese patients.     

Classification of first-episode schizophrenia patients and healthy subjects by automated MRI measures of regional brain volume and cortical thickness

Background

Although structural magnetic resonance imaging (MRI) studies have repeatedly demonstrated regional brain structural abnormalities in patients with schizophrenia, relatively few MRI-based studies have attempted to distinguish between patients with first-episode schizophrenia and healthy controls.

Method

Three-dimensional MR images were acquired from 52 (29 males, 23 females) first-episode schizophrenia patients and 40 (22 males, 18 females) healthy subjects. Multiple brain measures (regional brain volume and cortical thickness) were calculated by a fully automated procedure and were used for group comparison and classification by linear discriminant function analysis.

Results

Schizophrenia patients showed gray matter volume reductions and cortical thinning in various brain regions predominantly in prefrontal and temporal cortices compared with controls. The classifiers obtained from 66 subjects of the first group successfully assigned 26 subjects of the second group with accuracy above 80%.

Conclusion

Our results showed that combinations of automated brain measures successfully differentiated first-episode schizophrenia patients from healthy controls. Such neuroimaging approaches may provide objective biological information adjunct to clinical diagnosis of early schizophrenia.