Long-term effects of integrated cognitive behavioral therapy for chronic pain: A qualitative and quantitative study.

Cognitive behavioral therapy (CBT) is known to improve chronic pain management. However, past studies revealed only small to moderate benefits in short-term results, and long-term follow-up studies are lacking. This study aimed to follow an integrated CBT program's effectiveness 1.5 years after its completion. This observational study was the follow-up on the data collected from our CBT sessions conducted under 3 different studies in 2018 to 2019. Seven assessment items (Numerical Rating Scale, Pain Catastrophizing Scale [PCS], Pain Disability Assessment Scale [PDAS], Patient Health Questionnaire-9 items, Generalized Anxiety Disorder 7, European quality of life 5-dimensions 5-level, and Beck Depression Inventory [BDI]) were statistically analyzed. Thematic analysis was conducted in semi structured interviews. PCS ( F  = 6.52, P  = .003), PDAS ( F  = 5.68, P  = .01), European quality of life 5-dimensions 5-level ( F  = 3.82, P  = .03), and BDI ( F  = 4.61, P  = .01) exhibited significant changes ( P  < .05), confirmed by pairwise t test, revealing a moderate to large effect size. From post-treatment to follow-up, all scores showed no significant changes ( P  > .1). In the qualitative study, the analysis revealed 3 subthemes: "Autonomy," "Understanding of yourself and pain," and "Acceptance of pain." Our study suggests that integrated CBT may reduce the scores of PCS, PDAS and BDI, and this effect lasts for at least 1 year. Identified themes support the relevance of mitigative factors in managing chronic pain.

Attention and Imagery in Cognitive-Behavioral Therapy for Chronic Pain: An Exploratory Study.

Cognitive-behavioral therapy (CBT) has been shown to have a small to medium effect on chronic pain, necessitating further research to identify which components of CBT work for which type of patient. Previously, we developed a high-intensity individual CBT protocol and conducted a single-arm, uncontrolled feasibility study for chronic pain. In the current study, we explored patients' experiences in CBT sessions, including tactile attention-shift training; memory work using the peak-end rule; mental practice of action using motor imagery rescripting; and video feedback, including mirror therapy. Fourteen patients with chronic pain completed 16 CBT sessions. The tactile attention-shift training was very helpful for two patients and somewhat helpful for five, memory work was helpful for nine, mental practice was very helpful for four and somewhat helpful for three, and visual feedback was very helpful for six patients. Effective methodologies for new chronic pain CBT components should be developed. [Journal of Psychosocial Nursing and Mental Health Services, 60(5), 45-54.].

Clinical Effectiveness and Cost-effectiveness of Videoconference-Based Integrated Cognitive Behavioral Therapy for Chronic Pain: Randomized Controlled Trial.

BACKGROUND: Cognitive behavioral therapy is known to improve the management of chronic pain. However, the components of this therapy are still being investigated and debated. OBJECTIVE: This study aimed to examine the effectiveness of an integrated cognitive behavioral therapy program with new components (attention-shift, memory work, video feedback, and image training) delivered via videoconferencing. METHODS: This study was unblinded and participants were recruited and assessed face-to-face in the outpatient department. We conducted a randomized controlled trial for chronic pain to compare 16 weekly videoconference-based cognitive behavioral therapy (vCBT) sessions provided by a therapist with treatment as usual (TAU). Thirty patients (age range, 22-75 years) with chronic pain were randomly assigned to either vCBT (n=15) or TAU (n=15). Patients were evaluated at week 1 (baseline), week 8 (midintervention), and week 16 (postintervention). The primary outcome was the change in pain intensity, which was recorded using the numerical rating scale at 16 weeks from the baseline. Secondary outcomes were pain severity and pain interference, which were assessed using the Brief Pain Inventory. Additionally, we evaluated disability, pain catastrophizing cognition, depression, anxiety, quality of life, and cost utility. RESULTS: In the eligibility assessment, 30 patients were eventually randomized and enrolled; finally, 15 patients in the vCBT and 14 patients in the TAU group were analyzed. Although no significant difference was found between the 2 groups in terms of changes in pain intensity by the numerical rating scale scores at week 16 from baseline (P=.36), there was a significant improvement in the comprehensive evaluation of pain by total score of Brief Pain Inventory (-1.43, 95% CI -2.49 to -0.37, df=24; P=.01). Further, significant improvement was seen in pain interference by using the Brief Pain Inventory (-9.42, 95% CI -14.47 to -4.36, df=25; P=.001) and in disability by using the Pain Disability Assessment Scale (-1.95, 95% CI -3.33 to -0.56, df=24; P=.008) compared with TAU. As for the Medical Economic Evaluation, the incremental cost-effectiveness ratio for 1 year was estimated at 2.9 million yen (about US $25,000) per quality-adjusted life year gained. CONCLUSIONS: The findings of our study suggest that integrated cognitive behavioral therapy delivered by videoconferencing in regular medical care may reduce pain interference but not pain intensity. Further, this treatment method may be cost-effective, although this needs to be further verified using a larger sample size. TRIAL REGISTRATION: University Hospital Medical Information Network UMIN000031124; https://tinyurl.com/2pr3xszb.

Integrated cognitive behavioral therapy for chronic pain: An open-labeled prospective single-arm trial.

BACKGROUND: We aimed to examine the feasibility of our newly-developed, integrated, and high-intensity individual cognitive behavioral therapy (CBT) protocol for treatment-resistant chronic pain. METHODS: We conducted an open-labeled prospective single-arm trial for patients aged 18 years and above, suffering from chronic pain, and diagnosed with somatic symptom disorder with predominant pain. We provided 16 weekly sessions of CBT, each lasting for 50 minutes, which included 4 new strategies: attention shift, memory work, mental practice, and video feedback. For comparison, the study had a pre-test post-test design. The primary outcome was the change from baseline (week 1) to 16, as indicated by the Numerical Rating Scale and Pain Catastrophizing Scale. In addition, we evaluated depression, anxiety, disability, and quality of life as secondary outcomes. RESULTS: Sixteen patients with chronic pain underwent our CBT program. Though there was no reduction in pain intensity, catastrophic cognition showed statistically significant improvement with a large effect size. Depression, anxiety, and disability demonstrated statistically significant improvements, with small to moderate effect sizes. No adverse events were reported. CONCLUSION: Our newly integrated CBT program for chronic pain may improve catastrophic cognition, depression, anxiety, and disability. Large-scale randomized controlled studies are necessary to investigate the program's effectiveness in the future.

Comparison of brain activity between motor imagery and mental rotation of the hand tasks: a functional magnetic resonance imaging study.

Motor imagery (MI) has been considered effective in learning and practicing movements in many fields. However, when evaluating the effectiveness of this technique, the examiner has no way of assessing the participant's motor imagery process. As an alternative, we have been exploring a mental body-part rotation task, in which the examiner can estimate the participant's motivation and ability to sustain attention through the scored results. In this study, we aimed to investigate the possible application of a mental rotation (MRot) task and used fMRI to compare the brain activity during the MRot task with that during an MI task in healthy volunteers. Increased blood oxygenation level-dependent signals were observed bilaterally in the premotor areas and supplementary motor area during performance of both MI and MRot tasks. Our findings suggest that MRot could be an alternative to MI.

Exploratory study of imagery rescripting without focusing on early traumatic memories for major depressive disorder.

BACKGROUND: Mental imagery has a more powerful impact on our emotions than thinking in words about the same material. Treating intrusive images with imagery rescripting (IR) has been reported for various disorders, including post-traumatic stress disorder, social anxiety disorder, and bipolar disorder. There has been less research about IR as a major depressive disorder (MDD). AIMS: We examined whether IR without focusing on early traumatic memories is effective in MDD. METHODS: We enrolled 19 participants with MDD, who received 15 weekly sessions of full CBT, including two sessions for IR of intrusive images and, separately, for memory rescripting. Before and after the IR intervention, participants were asked to rate the intrusive images they experienced against, an intrusion index that included difficulty (interference with daily life), uncontrollability, distress caused by the negative image, and vividness. We recorded the contents of each participant's negative and positive imagery to classify these. RESULTS: The intrusion index scores decreased after the IR sessions. Negative images experienced by the participants while in a depressive mood were categorized into three different types: blame, social exclusion, and loneliness. The rescripted positive images were categorized into good relations and worthy self (competent self). CONCLUSIONS: These results suggest that IR of intrusive images without focusing on early traumatic memories may usefully be incorporated into routine CBT sessions for MDD.

Relationship between Oxidative Stress, Physical Activity, and Vitamin Intake in Patients with Asthma.

BACKGROUND: Oxidative stress plays an important role in the pathogenesis of bronchial asthma. Antioxidant nutrition and supplementation have been used to reduce oxidative stress. However, a clinical trial with antioxidant supplementation showed no beneficial effects in patients with asthma. On the other hand, physical activity is related to the prognosis of chronic obstructive pulmonary disease (COPD) and is also related to oxidant status. We investigated the relationships between oxidative stress, serum levels of vitamins, dietary vitamin intake, daily activities, and pulmonary functions in patients with asthma. METHODS: Eighteen patients with bronchial asthma were enrolled in this study. Reactive oxidative stress was assessed by measuring organic hydroperoxides (diacron reactive oxygen metabolites: dROM) in sera and by measuring H2O2 levels in exhaled breath condensates. The biological antioxidant capacity in serum was evaluated by measuring antioxidant potential capacity against ferric ion. We also assessed pulmonary functions, fraction of exhaled nitric oxide, serum levels of vitamins, dietary vitamin intake, and physical activities. RESULTS: There were no relationships between the index of oxidative stress (dROM and H2O2 in exhaled breathe condensates) and pulmonary functions, serum levels of vitamins, daily vitamin intakes, and activity levels in patients with asthma. CONCLUSION: The status of transient oxidative stress may not be related to daily activities, vitamin levels, and pulmonary functions in patients with asthma in a real-life setting. However, our results were obtained in the short-term period from a small number of subjects, so a large longitudinal study is required to ascertain the relationships between oxidative stress, physical activity and vitamin intake in patients with asthma.

Effects of five-minute internet-based cognitive behavioral therapy and simplified emotion-focused mindfulness on depressive symptoms: a randomized controlled trial.

BACKGROUND: Notwithstanding a high expectation for internet-based cognitive behavioral therapy (iCBT) for reducing depressive symptoms, many of iCBT programs have limitations such as temporary effects and high drop-out rates, possibly due to their complexity. We examined the effects of a free, simplified, 5-minute iCBT program by comparing it with a simplified emotion-focused mindfulness (sEFM) exercise and with a waiting list control group. METHODS: A total of 974 participants, who were recruited using the website of a market research company, were randomly assigned to the iCBT group, the sEFM group, and the control group. Those in the intervention arms performed each exercise for 5 weeks. The primary outcome measure was the Center for Epidemiological Studies Depression scale (CES-D) at postintervention. Secondary outcome measures were the Patient Health Questionnaire-9 (PHQ-9) and the Generalized Anxiety Disorder-7 scale (GAD-7). Intention-to-treat analyses were conducted. RESULTS: During postintervention assessment, there were no significant differences between the intervention arms and the control group in the CES-D, although the difference between the iCBT arm and control group was close to significance (p = 0.05) in favor of iCBT. There was a significant difference in the PHQ-9 in favor of the sEFM group compared with the control group. There were no significant differences in outcome measures between the three groups at the 6-week follow-up. CONCLUSIONS: Although both iCBT and sEFM have the potential to temporarily reduce depressive symptoms, substantial improvements are required to enhance and maintain their effects. TRIAL REGISTRATION: This trial is registered with the UMIN Clinical Trial Registry (UMIN-CTR) (ID: UMIN000015097 ) on 1 October 2014.

γ-Tocotrienol reduces human airway smooth muscle cell proliferation and migration.

AIMS: Vitamin E is an antioxidant that occurs in 8 different forms (α, ß, γ, and δ tocopherol and tocotrienol). Clinical trials of tocopherol supplementation to assess the impact of antioxidant activity in asthma have yielded equivocal results. Tocotrienol exhibits greater antioxidant activity than tocopherol in several biological phenomena in vivo and in vitro. We tested the effect of tocotrienol on human airway smooth muscle (ASM) cell growth and migration, both of which mediate airway remodeling in asthma. MAIN METHODS: We measured platelet-derived growth factor-BB (PDGF-BB)-induced ASM cell proliferation and migration by colorimetric and Transwell migration assays in the presence and absence of γ-tocotrienol (an isoform of tocotrienol). KEY FINDINGS: PDGF-BB-induced ASM cell proliferation and migration were inhibited by γ-tocotrienol. This effect was associated with inhibition of RhoA activation, but it had no effect on p42/p44 mitogen-activated protein kinase (MAPK) or Akt1 activation. We confirmed that pharmacological inhibition of Rho kinase activity was sufficient to inhibit PDGF-BB-induced ASM cell proliferation and migration. SIGNIFICANCE: γ-Tocotrienol could impart therapeutic benefits for airway remodeling in asthma by inhibiting human ASM cell proliferation and migration.

The effect of body position on pulmonary function, chest wall motion, and discomfort in young healthy participants.

OBJECTIVE: The purpose of this study was to investigate the effect of different recumbent positions on pulmonary function, chest wall motion, and feelings of discomfort in young nonobese healthy volunteers. METHODS: Twenty healthy volunteers (age, 28.0±1.4 years; height, 167.5±10.1 cm; weight, 62.3±10.2 kg) were studied in the sitting position and in the following 6 recumbent positions: supine, left retroversion at a 45° tilt, left anteversion at a 45° tilt, right retroversion at a 45° tilt, right anteversion at a 45° tilt, and prone. After 5 minutes of a selected position, pulmonary functions, including vital capacity (VC), forced expiratory volume in 1 second, maximal inspiratory and expiratory mouth pressures (MIP and MEP, respectively), and breathing pattern components at the chest wall were assessed. Discomfort was assessed using a modified Borg scale. RESULTS: When participants changed position from sitting to each of the 6 recumbent positions, forced expiratory volume in 1 second values decreased significantly (P < .05). None of the participants showed changes in the MIP or MEP in any of the 6 recumbent positions. Rib cage motion was restricted in all recumbent positions except supine, left anteversion at a 45° tilt, and prone. In all 6 recumbent positions, discomfort was experienced during the pulmonary tests. However, in the left retroversion at a 45° tilt position, no discomfort was experienced during the MIP and MEP assessments. CONCLUSION: In young, nonobese, healthy volunteers, recumbent positions caused diminished pulmonary functions and induced feelings of discomfort.

Methyl donor-deficient diet during development can affect fear and anxiety in adulthood in C57BL/6J mice.

DNA methylation is one of the essential factors in the control of gene expression. Folic acid, methionine and choline (methyl donors)--all nutrients related to one-carbon metabolism--are known as important mediators of DNA methylation. A previous study has shown that long-term administration of a diet lacking in methyl donors caused global DNA hypermethylation in the brain (Pogribny et al., 2008). However, no study has investigated the effects of a diet lacking in methyl donors during the developmental period on emotional behaviors such as fear and anxiety-like behavior in association with gene expressions in the brain. In addition, it has not been elucidated whether a diet supplemented with methyl donors later in life can reverse these changes. Therefore, we examined the effects of methyl donor deficiency during the developmental period on fear memory acquisition/extinction and anxiety-like behavior, and the relevant gene expressions in the hippocampus in juvenile (6-wk) and adult (12-wk) mice. We found that juvenile mice fed a methyl-donor-deficient diet had impaired fear memory acquisition along with decreases in the gene expressions of Dnmt3a and Dnmt3b. In addition, reduced anxiety-like behavior with decreased gene expressions of Grin2b and Gabar2 was observed in both the methyl-donor-deficient group and the body-weight-matched food-restriction group. After being fed a diet supplemented with methyl donors ad libitum, adult mice reversed the alteration of gene expression of Dnmt3a, Dnmt3b, Grin2b and Gabar2, but anxiety-like behavior became elevated. In addition, impaired fear-memory formation was observed in the adult mice fed the methyl-donor-deficient diet during the developmental period. Our study suggested that developmental alterations in the one-carbon metabolic pathway in the brain could have effects on emotional behavior and memory formation that last into adulthood.

Treatment outcome of high-dose image-guided intensity-modulated radiotherapy using intra-prostate fiducial markers for localized prostate cancer at a single institute in Japan.

BACKGROUND: Several studies have confirmed the advantages of delivering high doses of external beam radiotherapy to achieve optimal tumor-control outcomes in patients with localized prostate cancer. We evaluated the medium-term treatment outcome after high-dose, image-guided intensity-modulated radiotherapy (IMRT) using intra-prostate fiducial markers for clinically localized prostate cancer. METHODS: In total, 141 patients with localized prostate cancer treated with image-guided IMRT (76 Gy in 13 patients and 80 Gy in 128 patients) between 2003 and 2008 were enrolled in this study. The patients were classified according to the National Comprehensive Cancer Network-defined risk groups. Thirty-six intermediate-risk patients and 105 high-risk patients were included. Androgen-deprivation therapy was performed in 124 patients (88%) for a median of 11 months (range: 2-88 months). Prostate-specific antigen (PSA) relapse was defined according to the Phoenix-definition (i.e., an absolute nadir plus 2 ng/ml dated at the call). The 5-year actuarial PSA relapse-free survival, the 5-year distant metastasis-free survival, the 5-year cause-specific survival (CSS), the 5-year overall survival (OS) outcomes and the acute and late toxicities were analyzed. The toxicity data were scored according to the Common Terminology Criteria for Adverse Events, version 4.0. The median follow-up was 60 months. RESULTS: The 5-year PSA relapse-free survival rates were 100% for the intermediate-risk patients and 82.2% for the high-risk patients; the 5-year actuarial distant metastasis-free survival rates were 100% and 95% for the intermediate- and high-risk patients, respectively; the 5-year CSS rates were 100% for both patient subsets; and the 5-year OS rates were 100% and 91.7% for the intermediate- and high-risk patients, respectively. The Gleason score (<8 vs. ≥ 8) was significant for the 5-year PSA relapse-free survival on multivariate analysis (p = 0.044). There was no grade 3 or 4 acute toxicity. The incidence of grade 2 acute gastrointestinal (GI) and genitourinary (GU) toxicities were 1.4% and 8.5%, respectively. The 5-year actuarial likelihood of late grade 2-3 GI and GU toxicities were 6% and 6.3%, respectively. No grade 4 GI or GU late toxicity was observed. CONCLUSIONS: These medium-term results demonstrate a good tolerance of high-dose image-guided IMRT. However, further follow-up is needed to confirm the long-term treatment outcomes.

P50 suppression in human discrimination fear conditioning paradigm using danger and safety signals.

Auditory P50 suppression, which is assessed using a paired auditory stimuli (S1 and S2) paradigm to record the P50 mid-latency evoked potential, is assumed to reflect sensory gating. Recently, P50 suppression deficits were observed in patients with anxiety disorders, including panic disorder, post-traumatic stress disorder and obsessive-compulsive disorder, as we previously reported. The processes of fear conditioning are thought to play a role in the pathophysiology of anxiety disorders. In addition, we found that the P50 sensory gating mechanism might be physiologically associated with fear conditioning and extinction in a simple human fear-conditioning paradigm that involved a light signal as a conditioned stimulus (CS+). Our objective was to investigate the different patterns of P50 suppression in a discrimination fear-conditioning paradigm with both a CS+ (danger signal) and a CS- (safety signal). Twenty healthy volunteers were recruited. We measured the auditory P50 suppression in the control (baseline) phase, in the fear-acquisition phase, and in the fear-extinction phase using a discrimination fear-conditioning paradigm. Two-way (CSs vs. phase) Analysis of variance with repeated measures demonstrated a significant interaction between the two factors. Post-hoc LSD analysis indicated that the P50 S2/S1 ratio in the CS+ acquisition phase was significantly higher than that in the CS- acquisition phase. These results suggest that the auditory P50 sensory gating might differ according to the cognition of the properties (potentially dangerous or safe) of the perceived signal.

Pollen augments the influence of desert dust on symptoms of adult asthma patients.

BACKGROUND: East Asian desert dust storms that occur during mainly spring are called Asian dust storms (ADS). Our objective was to study the association of pollen and ADS with symptoms of adult asthma patients in Japan. METHODS: We designed a telephone survey to investigate the upper and lower respiratory, ocular, and skin symptoms of asthma patients during ADS in February, March, and December on 2009. Peak expiratory flow (PEF) was also measured from February to May. RESULTS: We surveyed 106 patients in February, 101 patients in March, and 103 patients in December. In February and March, Japanese cedar and/or cypress pollen was also in the atmosphere during ADS, but no pollen was identified during December survey. Worsening of upper or lower respiratory, ocular, or skin symptoms was noted by 20.8% of patients in February, 33.7% in March, and 16.5% in December. Worsening of symptoms was significantly more common in March than in February or December. Two patients needed emergency treatment for exacerbation during ADS in March, but no patient needed hospitalization in any period. There was no significant difference of the daily morning PEF/personal best PEF ratio between ADS days and control days. However, in patients with worsening of upper and/or lower respiratory tract symptoms, the daily morning PEF/personal best ratio was significantly associated with the atmospheric level of particulate matter, but not with levels of pollen or other air pollutants. CONCLUSIONS: Pollen augmented symptoms in adult asthma patients, but ADS on its own also were able to aggravate symptoms and pulmonary function.

Correlation between Asian dust storms and worsening asthma in Western Japan.

BACKGROUND: Severe wind storms during spring in East Asia, called Asian dust storms (ADS), have been assessed in the past for their effect on health in Asian countries. Our objective was to study the ADS association with asthma symptoms in adult patients in Japan. METHODS: We designed a telephone survey to assess ADS influence on upper and lower respiratory, ocular and cutaneous symptoms in 98 patients with adult asthma from April to May 2007. Peak expiratory flow (PEF) was also measured from February to May. RESULTS: Worsening lower respiratory symptoms were noted by 22 of 98 patients during ADS in April, when Japanese cedar pollen levels also increased. During ADS in May, however, Japanese cedar and cypress pollen levels were not elevated, 11 patients had worsening of lower respiratory symptoms. None required emergency treatment for the exacerbation. Lower respiratory symptoms worsening most were cough and sputum; this was more common in patients with allergic rhinitis or atopy than in those without (P < 0.05). Min%Max differed significantly at 88.7 ± 6.6% during dust dispersion period, defined as the ADS day plus the next 6 days, versus 92.0 ± 5.3% during the 7-day period before a dust storm. CONCLUSIONS: We found that ADS aggravated lower respiratory symptoms in adult patients with asthma, but this influence was mild.

Asthma: Chronopharmacotherapy and the molecular clock.

Bronchial asthma is characterized by chronic airways inflammation and reversible airflow limitation. In patients with asthma, symptoms generally worsen during the early hours of the morning, and pulmonary function often deteriorates at the same time, suggesting a role for chronopharmacotherapy. Several drugs for asthma have been developed based on chronopharmacology. Most medications employed for the chronotherapy of asthma are administered once at night with the goal of preventing chronic airway inflammation or development of airflow limitation. In addition to bronchodilators, the inhaled glucocorticosteroid ciclesonide is now available with once-daily dosing, which also improves patients' compliance. Numerous investigations have demonstrated the usefulness of chronotherapy for asthma, especially for patients with nocturnal asthma. This review focuses on chronotherapy of asthma, and also provides a molecular biological explanation for the influence of asthma medications on the clock genes.

Enhancement of acoustic prepulse inhibition by contextual fear conditioning in mice is maintained even after contextual fear extinction.

Prepulse inhibition (PPI) of the acoustic startle response is one of the few and major paradigms for investigating sensorimotor gating systems in humans and rodents in a similar fashion. PPI deficits are observed not only in patients with schizophrenia, but also in patients with anxiety disorders. Previous studies have shown that PPI in rats can be enhanced by auditory fear conditioning. In this study, we evaluated the effects of contextual fear conditioning (FC) for six times a day and fear extinction (FE) for seven days on PPI in mice. C57BL/6J mice (male, 8-12 weeks) were divided into three groups; no-FC (control), FC and FC + FE. We measured PPI at the following three time points, (1) baseline before FC, (2) after FC, and (3) after FE. The results showed that PPI was increased after FC. Moreover, the enhanced PPI following FC was observed even after FE with decreased freezing behaviors. These results suggested contextual fear conditioning could enhance acoustic PPI, and that contextual fear extinction could decrease freezing behaviors, but not acoustic PPI.

Dopaminergic hypofunctions and prepulse inhibition deficits in mice lacking midkine.

Midkine is a 13-kDa retinoic acid-induced heparin-binding growth factor involved in various biological phenomena such as cell migration, neurogenesis, and tissue repair. We previously demonstrated that midkine-deficient (Mdk(-/-)) mice exhibited a delayed hippocampal development with impaired working memory and increased anxiety only at the age of 4 weeks. To assess whether midkine gene could play important roles in development and maintenance of central nervous system, we investigated biochemical and behavioral parameters in dopamine and glutamate neurotransmission of Mdk(-/-) mice. The Mdk(-/-) mice exhibited a hypodopaminergic state (i.e., decreased levels of dopamine and its receptors in the striatum) with no alterations of glutamatergic system (i.e., normal level of glutamate, glutamine, glycine, d-serine, l-serine, and NMDA receptors in the frontal cortex and hippocampus). We also found prepulse inhibition deficits reversed by clozapine and haloperidol in the Mdk(-/-) mice. Our results suggested that midkine deficiency may be related to neurochemical and behavioral dysfunctions in dopaminergic system.

A comparative study of the effects of erabu sea snake (Laticauda semifasciata) lipids, green tea extract and conjugated linoleic acid on the swimming endurance of mice.

The aim of this study was to assess the interaction between physical and biochemical parameters in mice fed 1 % sea snake lipids (SSL) and compare these with animals fed diets containing 0.2 % green tea extract (GTE) or 0.5 % conjugated linoleic acid (CLA). The swimming times of the SSL group were significantly increased at Weeks 12 and 16 (p<0.001), and those of the GTE group, at Week 12 (p<0.005), but not those of the control or CLA group, compared with those at Week 0. The increase tended to be significant in the SSL group compared with the control group at Week 12 (p=0.09). Both the SSL and GTE groups had significantly longer swimming times than the CLA group at Weeks 12 and 16 (p<0.001). After 5 minutes of swimming exercise, the SSL group exhibited significantly lower levels of plasma and muscle lactates (p<0.01), and plasma non-esterified fatty acid (NEFA) (p<0.001) than the control group. There were no significant differences in any of plasma glucose, muscle and liver glycogens, muscle lactate dehydrogenase (LDH), carnitine palmitoyltransferase (CPT), or monocarboxylate transporter 1 (MCT1) between SSL and control groups. The results suggest that the intake of 1 % SSL improved endurance more than the intake of 0.2 % GTE or 0.5 % CLA in mice. This action may involve the promotion of lactate oxidation for utilization.

Dexamethasone interferes with trastuzumab-induced cell growth inhibition through restoration of AKT activity in BT-474 breast cancer cells.

The combination of trastuzumab with paclitaxel (PTX) is an important option for the treatment of HER2-positive breast cancer. Dexamethasone (Dex) premedication is routinely used in the treatment with PTX. The interactions among Dex, PTX and trastuzumab were evaluated in BT-474 cells. Dex interfered with trastuzumab-induced cell growth inhibition without clear effects on PTX-induced cytotoxicity. Trastuzumab dephosphorylated retinoblastoma protein (pRB). Dex restored this trastuzumab-induced dephosphorylation of pRB and released trastuzumab-induced G1 arrest. Trastuzumab suppressed AKT activity without affecting ERK activity. A specific inhibitor for the phosphatidylinositol 3-kinase/AKT pathway, LY294002, inhibited cell growth and AKT and pRB phosphorylation. Dex restored the trastuzumab-induced suppression of AKT without affecting ERK activity. It was concluded that Dex interferes with trastuzumab-induced cell growth inhibition, at least partially, through the restoration of trastuzumab-induced AKT suppression and subsequent pRB dephosphorylation in BT-474 breast cancer cells. These observations support the development of new chemotherapeutic regimens without glucocorticoid premedication.