Factors associated with early discontinuation of anamorelin in patients with cancer-associated cachexia.

PURPOSE: Cancer-associated cachexia, a multifactorial syndrome involving loss of muscle mass and anorexia, is an unremitting problem for cancer patients. Anamorelin has become available for cancer-associated cachexia, but early discontinuation is common in clinical practice. This study aimed to explore factors related to the early discontinuation of anamorelin and its relationship to survival. PATIENTS AND METHODS: This prospective, observational study of multimodal clinical practice involved patients who took anamorelin (100 mg) for cancer-associated cachexia at Aichi Medical University Hospital between 14 May 2021 and 31 March 2022. In July 2022, clinical data were extracted from electronic clinical records. Patients who discontinued anamorelin less than 4 weeks after initiation were defined as the early discontinuation group, and their clinical data and survival time were compared with those of the continuation group. This study was approved by the Ethics Committee of the university (approval no. 2021-124). RESULTS: Of the 42 patients treated with anamorelin, 40 (median age 72.5 years, median BMI 18.7 kg/m2) were analyzed, including 13 with non-small cell lung cancer, and 12 with pancreatic, 8 with colorectal, and 7 with gastric cancers. On univariate analysis, the early discontinuation group included more patients with worse performance status (PS) (p=0.028), low prognostic nutritional index (PNI) (p=0.001), and no concomitant anticancer drugs (p=0.003). On multivariate analysis, PS and PNI were related to anamorelin continuation. Survival time was significantly shorter in the early discontinuation group (p=0.039). CONCLUSION: Worse PS and low PNI were associated with early discontinuation of anamorelin. Longer survival time was observed in the continuation group.

Structure activity relationship of N-1 substituted 1,5-naphthyrid-2-one analogs of oxabicyclooctane-linked novel bacterial topoisomerase inhibitors as broad-spectrum antibacterial agents (Part-9).

Novel bacterial topoisomerase inhibitors (NBTIs) are the newest members of gyrase inhibitor broad-spectrum antibacterial agents, represented by the most advanced member, gepotidacin, a 4-amino-piperidine linked NBTI, which is undergoing phase III clinical trials for treatment of urinary tract infections (UTI). We have extensively reported studies on oxabicyclooctane linked NBTIs, including AM-8722. The present study summarizes structure activity relationship (SAR) of AM-8722 leading to identification of 7-fluoro-1-cyanomethyl-1,5-naphthyridin-2-one based NBTI (16, AM-8888) with improved potency and spectrum (MIC values of 0.016-4 µg/mL), with Pseudomonas aeruginosa being the least sensitive strain (MIC 4 µg/mL).

In Vitro and In Vivo Characterization of the Novel Oxabicyclooctane-Linked Bacterial Topoisomerase Inhibitor AM-8722, a Selective, Potent Inhibitor of Bacterial DNA Gyrase.

Oxabicyclooctane-linked novel bacterial topoisomerase inhibitors (NBTIs) represent a new class of recently described antibacterial agents with broad-spectrum activity. NBTIs dually inhibit the clinically validated bacterial targets DNA gyrase and topoisomerase IV and have been shown to bind distinctly from known classes of antibacterial agents directed against these targets. Herein we report the molecular, cellular, and in vivo characterization of AM-8722 as a representative N-alkylated-1,5-naphthyridone left-hand-side-substituted NBTI. Consistent with its mode of action, macromolecular labeling studies revealed a specific effect of AM-8722 to dose dependently inhibit bacterial DNA synthesis. AM-8722 displayed greater intrinsic enzymatic potency than levofloxacin versus both DNA gyrase and topoisomerase IV from Staphylococcus aureus and Escherichia coli and displayed selectivity against human topoisomerase II. AM-8722 was rapidly bactericidal and exhibited whole-cell activity versus a range of Gram-negative and Gram-positive organisms, with no whole-cell potency shift due to the presence of DNA or human serum. Frequency-of-resistance studies demonstrated an acceptable rate of resistance emergence in vitro at concentrations 16- to 32-fold the MIC. AM-8722 displayed acceptable pharmacokinetic properties and was shown to be efficacious in mouse models of bacterial septicemia. Overall, AM-8722 is a selective and potent NBTI that displays broad-spectrum antimicrobial activity in vitro and in vivo.

Structure activity relationship of C-2 ether substituted 1,5-naphthyridine analogs of oxabicyclooctane-linked novel bacterial topoisomerase inhibitors as broad-spectrum antibacterial agents (Part-5).

Oxabicyclooctane linked novel bacterial topoisomerase inhibitors (NBTIs) are new class of recently reported broad-spectrum antibacterial agents. They target bacterial DNA gyrase and topoisomerase IV and bind to a site different than quinolones. They show no cross-resistance to known antibiotics and provide opportunity to combat drug-resistant bacteria. A structure activity relationship of the C-2 substituted ether analogs of 1,5-naphthyridine oxabicyclooctane-linked NBTIs are described. Synthesis and antibacterial activities of a total of 63 analogs have been summarized representing alkyl, cyclo alkyl, fluoro alkyl, hydroxy alkyl, amino alkyl, and carboxyl alkyl ethers. All compounds were tested against three key strains each of Gram-positive and Gram-negative bacteria as well as for hERG binding activities. Many key compounds were also tested for the functional hERG activity. Six compounds were evaluated for efficacy in a murine bacteremia model of Staphylococcus aureus infection. Significant tolerance for the ether substitution (including polar groups such as amino and carboxyl) at C-2 was observed for S. aureus activity however the same was not true for Enterococcus faecium and Gram-negative strains. Reduced clogD generally showed reduced hERG activity and improved in vivo efficacy but was generally associated with decreased overall potency. One of the best compounds was hydroxy propyl ether (16), which mainly retained the potency, spectrum and in vivo efficacy of AM8085 associated with the decreased hERG activity and improved physical property.

Structure activity relationship of substituted 1,5-naphthyridine analogs of oxabicyclooctane-linked novel bacterial topoisomerase inhibitors as broad-spectrum antibacterial agents (Part-4).

Bacterial resistance is rapidly growing, necessitating the need to discover new agents. Novel bacterial topoisomerase inhibitors (NBTIs) are new class of broad-spectrum antibacterial agents targeting bacterial DNA gyrase and topoisomerase IV. This class of inhibitors binds to an alternative binding site relative to fluoroquinolones and shows no cross-resistance to quinolones. NBTIs consist of three structural motifs. A structure activity relationship of the left hand motif 1,5-naphthyridine of oxabicyclooctane-linked NBTIs is described. Fifty five compounds were evaluated against a panel of key Gram-positive and Gram-negative strains of bacteria, as well as for hERG activity and five compounds were tested for in vivo efficacy in murine model of Staphylococcus aureus infection. These studies suggest that only a narrow range (activating and deactivating) of substitutions at C-2 and C-7 are tolerated for optimal antibacterial activity and spectrum. An alkoxy (methoxy) and CN at C-2, and a halogen and hydroxyl at C-7, appeared to be preferred in this series. Substitutions on the other three carbons generally have detrimental effect on the activity. No clear hERG activity SAR emerged from these substitutions.

Hydroxy tricyclic 1,5-naphthyridinone oxabicyclooctane-linked novel bacterial topoisomerase inhibitors as broad-spectrum antibacterial agents-SAR of RHS moiety (Part-3).

Novel bacterial topoisomerase inhibitors (NBTIs) are a new class of broad-spectrum antibacterial agents targeting bacterial Gyrase A and ParC and have potential utility in combating antibiotic resistance. (R)-Hydroxy-1,5-naphthyridinone left-hand side (LHS) oxabicyclooctane linked pyridoxazinone right-hand side (RHS) containing NBTIs showed a potent Gram-positive antibacterial profile. SAR around the RHS moiety, including substitutions around pyridooxazinone, pyridodioxane, and phenyl propenoids has been described. A fluoro substituted pyridoxazinone showed an MIC against Staphylococcus aureus of 0.5 µg/mL with reduced functional hERG activity (IC50 333 µM) and good in vivo efficacy [ED90 12 mg/kg, intravenous (iv) and 15 mg/kg, oral (p.o.)]. A pyridodioxane-containing NBTI showed a S. aureus MIC of 0.5 µg/mL, significantly improved hERG IC50 764 µM and strong efficacy of 11 mg/kg (iv) and 5 mg/kg (p.o.). A phenyl propenoid series of compounds showed potent antibacterial activity, but also showed potent hERG binding activity. Many of the compounds in the hydroxy-tricyclic series showed strong activity against Acinetobacter baumannii, but reduced activity against Escherichia coli and Pseudomonas aeruginosa. Bicyclic heterocycles appeared to be the best RHS moiety for the hydroxy-tricyclic oxabicyclooctane linked NBTIs.

[Nationally representative score of the Japanese language version of the 13-item 7-point sense of coherence scale].

OBJECTIVES: The amount of research relating to evaluation of intervention programs with regard to sense of coherence, a concept of salutogenic stressor coping capacity, is increasing in Japan. However, a nationally representative score of the Japanese version of the sense of coherence scale has not yet been reported. The aim of this study was to describe the 13-item, 7-point Japanese sense of coherence scale (SOC-13), with scoring by sex and age group, and to examine the relationships between the score and locality and city size. METHODS: Four thousand Japanese men and women were selected by stratified random sampling, and a cross-sectional, self-administered questionnaire survey was conducted using the placement method. Responses were obtained from 2,067 individuals (response rate: 51.7%). This study analyzed 956 men and 1,107 women (mean age [standard deviation]: 50.0 [14.3]). RESULTS: The mean score on the SOC-13 was 59.0 (12.2) in all participants, 59.1 (11.8) in men, and 58.9 (12.5) in women. No significant difference was found between men and women (P=0.784). ANOVA and multiple comparison for age difference showed a clear relationship (P<0.05) between higher age and a higher SOC-13 score. Moreover, the results of main and interaction effects in ANCOVA, with independent variables for locality (11 segments) and city size (four segments), were not significant when controlled for age. CONCLUSION: A nationally representative score for the Japanese SOC-13 was acquired. In future research, application of the SOC-13 in Japan for clinical studies is anticipated based on the nationally representative score.

A sense of coherence (SOC) among the fathers of children with chronic illnesses.

AIM: This study focuses on the fathers of children with chronic illnesses in an effort to clarify how the stressor and the father's sense of coherence (SOC) influence their mental health and how the father's SOC is associated with the social support. DESIGN: Cross-sectional study. METHODS: We conducted a self-reported questionnaire survey of 137 respondents (51 fathers of children with chronic illnesses, 86 fathers of healthy children) were statistically using ANOVA. RESULTS: The fathers' stressor was significantly related to their SOC. Furthermore, the SOC of the fathers majorly influenced their mental health, while having a buffering effect on the stressor with respect to depression. And their SOC was significantly positively associated with the social support. Our findings underscore that father's SOC has a buffering effect on self-mental health and is important for maintaining mental health and enhancing SOC to reduce the stressors of these fathers with respect to depression.

Validity of the diagnostic criteria from the Asian Working Group for Cachexia in advanced cancer.

BACKGROUND: Recently, the Asian Working Group for Cachexia (AWGC) published a consensus statement on diagnostic criteria for cachexia in Asians. We aimed to validate the criteria in adult patients in Japan with advanced cancer. METHODS: We conducted a single-institution retrospective cohort study between April 2021 and October 2022. The AWGC criteria include chronic comorbidities and either a weight loss of >2% over 3-6 months or a body mass index (BMI) of <21 kg/m2 . In addition, any of the following items were required: anorexia as a subjective symptom, decreased grip strength as an objective measurement and an elevated C-reactive protein (CRP) level as a biomarker. We used the cut-off value of grip strength of 28/18 kg for male/female individuals and CRP level of 5 mg/L. RESULTS: Of the 449 consecutive patients, 85 of those who could not be evaluated because of end-of-life or refractory symptoms (n = 41) or missing data (n = 44) were excluded from the primary analysis. The prevalence of the AWGC-defined cachexia was 76% (n = 277), and the median survival time (MST) for all patients was 215 (95% confidence interval [CI] 145-270) days. The prevalence of the following criteria was significantly higher in patients with cachexia than in those without cachexia: a BMI of <21 kg/m2 (65% vs. 15%, P < 0.001), a weight loss of >2% in 6 months (87% vs. 14%, P < 0.001), anorexia (75% vs. 47%, P < 0.001), a grip strength of <28 kg in male individuals (63% vs. 28%, P < 0.001) and CRP level of >5 mg/L (85% vs. 56%, P < 0.001). Overall survival was significantly shorter in patients with cachexia than in those without cachexia (MST 157 days, 95% CI 108-226 days vs. MST 423 days, 95% CI 245 days to not available, P = 0.0023). The Cox proportional hazards analysis showed that best supportive care (hazard ratio [HR] 2.91, P ≤ 0.001), lung cancer (HR 1.67, P = 0.0046), an Eastern Cooperative Oncology Group Performance Status score of ≥3 (HR 1.58, P = 0.016), AWGC-defined cachexia (HR 1.56, P = 0.015), an age of ≥70 years (HR 1.53, P = 0.0070), oedema (HR 1.31, P = 0.022) and head/neck cancer (HR 0.44, P = 0.023) were found to be the significant predictors for mortality. CONCLUSIONS: We demonstrated that AWGC-defined cachexia has a significant prognostic value in advanced cancer.

Folate-appended ß-cyclodextrin as a promising tumor targeting carrier for antitumor drugs in vitro and in vivo.

A large number of antitumor drug delivery carriers based on passive targeting and/or active targeting have been developed. However, encapsulation of antitumor drugs into these drug carriers is often complicated, and antitumor activities of these targeting systems are not satisfactory. In the present study, we first prepared heptakis-6-folic acid (FA)-appended ß-cyclodextrin (ß-CyD) possessing two caproic acids between FA and a ß-CyD molecule as a spacer (Fol-c(2)-ß-CyD) and evaluated the potential as a novel tumor targeting carrier for antitumor drugs through a complexation. Fol-c(2)-ß-CyD formed an inclusion complex with doxorubicin (DOX) at a 1:1 molar ratio with a markedly high stability constant (>10(6) M(-1)). Cellular uptake of DOX was increased by the addition of Fol-c(2)-ß-CyD in KB cells, a folate receptor-α (FR-α)-positive cell line. Additionally, Fol-c(2)-ß-CyD increased in vitro antitumor activities of antitumor drugs such as DOX, vinblastine (VBL), and paclitaxel (PTX) in KB cells, but not in A549 cells, a FR-α-negative cell line. The complex of DOX with Fol-c(2)-ß-CyD markedly increased antitumor activity of DOX, not only after intratumoral administration but also after intravenous administration to mice subcutaneously inoculated Colon-26 cells, a FR-α-positive cell line. These findings suggest that Fol-c(2)-ß-CyD could be useful as a promising antitumor drug carrier.

Design and evaluation of folate-appended α-, ß-, and γ-cyclodextrins having a caproic acid as a tumor selective antitumor drug carrier in vitro and in vivo.

We reported that per-6-folic acid (FA)-appended ß-cyclodextrin (ß-CyD) possessing two caproic acids between FA and a ß-CyD molecule as a spacer (Fol-c2-ß-CyD) could be useful as a promising antitumor drug carrier. However, the effects of the cavity size and the spacer length on the carrier ability are not still known. In this study, we designed and evaluated the FA-appended three kinds of CyDs possessing a caproic acid as a spacer between FA and a CyD molecule (Fol-c1-CyDs) as a tumor targeting carrier for antitumor drugs. The stability constant of the Fol-c1-ß-CyD/doxorubicin (DOX) complex was much higher than those of Fol-c1-α-CyD and Fol-c1-γ-CyD at pH 7.3. Antitumor activity of DOX was increased by the complexation with Fol-c1-ß-CyD, but not with Fol-c1-α-CyD or Fol-c1-γ-CyD in KB cells, a folate receptor-α-positive cell line. Also, Fol-c1-ß-CyD increased antitumor activities of paclitaxel and vinblastine, but not 5-fluorouracil. Furthermore, Fol-c1-ß-CyD accelerated cellular uptake of DOX and inhibited its efflux from KB cells. The Fol-c1-ß-CyD/DOX complex showed much higher antitumor activity than DOX alone after intratumoral and intravenous administrations to tumor-bearing mice with a negligible change of the blood chemistry values. These findings suggest that Fol-c1-ß-CyD could be useful as a tumor-selective carrier for antitumor drugs.

[Change of the patient characteristics among adult asthmatics hospitalized due to acute exacerbation].

BACKGROUND: We analysed the patient characteristics among adult asthmatics hospitalized to our hospital to clearfy the residual problems in the prevention and treatment of asthma. METHODS: We identified the adult asthmatics hospitalized to our hospital during the period A: Jan 2004-Dec 2005 and the period B: Jan 2009-Dec2010 and analysed retrospectively around age, smoking history, and the use of ICS (including combination medicine) and so on. RESULTS: The total patient numbers were A: 161 and B: 88, decreasing to almost half. The rates of the patients older than 65 years were equivalent between the 2 groups. Categorized according to age, in the group <65 years old, the rates of ICS use were A: 22.9% and B: 35.8% and the current smoking rates were A: 42.7% and B: 49.1% respectively. In the group 65≤ years old, the rates of ICS use were A: 46.2% and B: 48.6%, and the current smoking rates were A: 19.7% and B: 22.9%. CONCLUSION: In the group <65 years old, ICS has become more popular but smoking rate has increased among hospitalized adult asthmatics. It is estimated that smoking leads to reduce the effect of ICS and the strategy of smoking cessation will be needed to reduce acute exacerbations. In the group 65≤ years old, ICS is relatively more popular than youth and smoking rate is limited. Asthma among elder people may be refractory and more efficient strategies must be required.

Cachexia staging score predicts survival in patients with cancer who receive palliative care.

OBJECTIVE: The aim of this study was to validate the cachexia staging score (CSS), a multidimensional, item-based diagnostic method of cachexia severity, for patients with advanced cancer receiving palliative care. METHODS: Eligible patients were those with cancer who received palliative care during hospitalization between May 2019 and April 2020. All data were collected retrospectively from medical records. Cachexia was graded into four levels according to the CSS. Kaplan-Meier curves were constructed with or without death as the outcome, comparing prognoses among different levels of cachexia with Bonferroni correction. Cox proportional hazards regression analysis was performed to identify factors affecting mortality. RESULTS: The mean age of the 196 patients was 65.8 ± 14 y. Men made up 42% of the study population. Lower body mass index, increased rate of weight loss, increased strength, assistance walking, rising from a chair, climbing stairs, and falls (SARC-F) points, decline in activities of daily living, appetite loss, and abnormal blood biomarkers were significantly more common with increasing severity of cachexia, and survival was shorter (P < 0.001). The hazard ratio (HR) increased with worsening severity of cachexia according to CSS classification (precachexia: HR, 2.78; 95% confidence interval [CI], 0.62-12.46, P = 0.182; cachexia: HR, 4.77; 95% CI, 1.09-20.80; P = 0.038; and refractory cachexia: HR, 11.00; 95% CI, 2.37-51.07; P = 0.002). CONCLUSIONS: The CSS predicted life expectancy in a population of patients receiving palliative care and had excellent prognostic discriminative power to classify patients at different stages of cachexia.

Folate-PEG-appended dendrimer conjugate with α-cyclodextrin as a novel cancer cell-selective siRNA delivery carrier.

We previously reported that of the various polyamidoamine (PAMAM) STARBURST dendrimer (generation 3, G3) (dendrimer) conjugates with cyclodextrins (CyDs), the dendrimer (G3) conjugate with α-CyD having an average degree of substitution of 2.4 (α-CDE (G3)) has the greatest potential for a novel carrier for siRNA in vitro and in vivo. To improve the siRNA transfer activity and the lack of target specificity of α-CDE (G3), we prepared folate-polyethylene glycol (PEG)-appended α-CDEs (G3) (Fol-PαCs) with various degrees of substitution of folate (DSF) and evaluated their siRNA transfer activity to folate receptor (FR)-overexpressing cancer cells in vitro and in vivo. Of the three Fol-PαCs (G3, DSF 2, 4 and 7), Fol-PαC (G3, DSF 4) had the highest siRNA transfer activity in KB cells (FR-positive). Fol-PαC (G3, DSF 4) was endocytosed into KB cells through FR. No cytotoxicity of the siRNA complex with Fol-PαC (G3, DSF 4) was observed in KB cells (FR-positive) or A549 cells (FR-negative) up to the charge ratio of 100/1 (carrier/siRNA). In addition, the siRNA complex with Fol-PαC (G3, DSF 4) showed neither interferon response nor inflammatory response. Importantly, the siRNA complex with Fol-PαC (G3, DSF 4) tended to show the in vivo RNAi effects after intratumoral injection and intravenous injection in tumor cells-bearing mice. The FITC-labeled siRNA and TRITC-labeled Fol-PαC (G3, DSF 4) were actually accumulated in tumor tissues after intravenous injection in the mice. In conclusion, the present results suggest that Fol-PαC (G3, DSF 4) could potentially be used as a FR-overexpressing cancer cell-selective siRNA delivery carrier in vitro and in vivo.

[Role of brain 5-HT7 receptors as a functional molecule involved in the development of stress adaptation].

A growing body of evidence suggests that the brain serotonin (5-HT) nervous system is an important component related to the etiology as well as the treatment of stress-related psychiatric disorders. Molecular cloning studies have revealed the existence of 14 different genes, each encoding a distinct 5-HT receptor subtype. The 5-HT7 receptor is the most recently identified member of the 5-HT receptor subtypes, and the physiological role of this receptor is still unknown. Recently, either selective agonists or antagonists for 5-HT7 receptors, as well as 5-HT7 receptor knockout mice, have been developed, and these have recently been used as the experimental tools for determining the actual function of 5-HT7 receptors. The first half of the present article introduces the reports that have examined the role of the 5-HT7 receptor on emotional regulation. On the other hand, it has been indicated that the ability to adapt to stress is an important defensive function of a living body, and impairment of this ability may contribute to some stress-related disorders. Thus, the examination of brain mechanisms involved in stress adaptation could help to pave the way for new therapeutic strategies for stress-related psychiatric disorders. The second half of the present article introduces our recent studies focusing on the relationship between brain 5-HT7 receptors and the mechanisms of stress adaptation.

Handwriting Features of Multiple Drawing Tests for Early Detection of Alzheimer's Disease: A Preliminary Result.

Early detection of Alzheimer's disease (AD) has become increasingly important. Healthy monitoring technology focusing on behavioral changes is a promising approach in this vein. Among such technologies, handwriting features measured by digital tablet devices have attracted attention as potential indicators for detecting AD and mild cognitive impairment (MCI). However, previous studies have mainly investigated features in single tasks, and it remains unclear whether combining the features of multiple tasks could improve the performance of detecting AD and MCI. In this study, we investigated features in five representative tasks used in neuropsychological tests collected from 71 seniors including some diagnosed with MCI and AD. We found that our three-class classification model improved diagnosis accuracy by up to 11.3% by combining features of multiple tasks, for a final accuracy of 74.6%. We also suggested that drawing behaviors during multiple tasks might be useful for estimating disease progression simply by utilizing the labels of disease groups.

Multimodal Behavior Analysis Towards Detecting Mild Cognitive Impairment: Preliminary Results on Gait and Speech.

Behavioral analysis for identifying changes in cognitive and physical functioning is expected to help detect dementia such as mild cognitive impairment (MCI) at an early stage. Speech and gait features have been especially recognized as behavioral biomarkers for dementia that possibly occur early in its course, including MCI. However, there are no studies investigating whether exploiting the combination of multimodal behavioral data could improve detection accuracy. In this study, we collected speech and gait behavioral data from Japanese seniors consisting of cognitively healthy adults and patients with MCI. Comparing the models using single modality behavioral data, we showed that the model using multimodal behavioral data could improve detection by up to 5.9%, achieving 82.4% accuracy (chance 55.9%). Our results suggest that the combination of multimodal behavioral features capturing different functional changes resulting from dementia might improve accuracy and help timely diagnosis at an early stage.

[Pharmacological characterization and mechanisms of the novel antidepressive- and/or anxiolytic-like substances identified from Perillae Herba].

The leaves of Perilla frutescens Britton var. acuta Kudo (Perillae Herba) are commonly found in traditional oriental herbal medicines, which are primarily used to treat depression and anxiety-related disorders. We have recently identified rosmarinic acid as well as its major metabolite caffeic acid as novel antidepressive and/or anxiolytic-like substances from components within Perillae Herba. The present article will review our previous findings and also provide a view of future studies. Behavioral as well as analytical studies have demonstrated that first, the extracts from Perillae Herba, which produced an antidepressive-like effect in the forced swimming test, contained abundant rosmarinic acid; second, the extracts from another species of Perillae Herba, which contains only low levels of rosmarinic acid, did not have an antidepressive-activity; third, rosmarinic acid and caffeic acid themselves also produced an antidepressive-like effect; finally, both compounds showed an anxiolytic-like activity in the conditioned fear stress test. Neurochemical studies have also revealed that neither rosmarinic acid nor caffeic acid affects the uptake of monoamines or monoamine oxidase activity, which may underlie the therapeutic value of existing clinically effective antidepressants. Furthermore, it has been found in the recent study that caffeic acid produces antidepressive- and/or anxiolytic-like effects through the modulation of the alpha1A-adrenoceptor-mediated signal transductions and also attenuates the down-regulation of BDNF transcription that results from the exposure to forced swimming stress. These results suggest that rosmarinic acid and caffeic acid may produce antidepressive- and/or anxiolytic-like effects via some mechanism(s) other than those of drugs that now clinically used. Therefore, further studies on the mechanisms involved in the antidepressive- and/or anxiolytic-like properties of both substances could help to explain the pathophysiology underlying depression and anxiety disorders, and pave the way for the development of new therapeutic drugs.

Awareness of malalignment and malocclusion in children and their guardians.

We conducted a survey on the awareness of abnormalities of dentition and occlusion in 1,904 children (0-15 years old) and their guardians (parents, grandmothers, grandfathers and siblings) on their initial visit to the Department of Pediatric Dentistry, Chiba Hospital, Tokyo Dental College. The location and type of abnormality for which the children and their guardians most commonly sought treatment were crowding of the upper and lower anterior teeth and inverted occlusion. The most common initial triggers for concern were "guardians noticed abnormalities themselves". It seems logical that where malocclusions that children and guardians can easily notice for themselves are present, they are likely to make an early visit to a clinic in the hope of improving the abnormality. We suggest that further effect is made to educate guardians of children with abnormalities of dentition and occlusion on the importance of obtaining treatment.

Role of Src family kinase in the rewarding effect and hyperlocomotion induced by morphine.

The aim of the present study was to investigate the effect of a selective Src family kinase inhibitor, 4-amino-5-(4-chlorophenyl)-(t-butyl)pyrazolo[3,4-D]pyrimidine (PP2), on the rewarding effect and hyperlocomotion induced by morphine. An intracerebroventricular pretreatment with PP2 (0.1-10 nmol/mouse) significantly suppressed the morphine-induced rewarding effect and hyperlocomotion in a dose-dependent manner. We also investigated the changes in immunoreactivities to phosphorylated-Src family kinase in the nucleus accumbens of mice showing the morphine-induced rewarding effect. We found for the first time that Src family kinase is activated in the nucleus accumbens of mice showing the morphine-induced rewarding effect as compared with that found in saline-treated control mice. These findings suggest that Src family kinases in the nucleus accumbens are involved in the rewarding effect and hyperlocomotion induced by morphine.