Mindfulness-Based Cognitive Therapy for Late-Life Depression: a Randomised Controlled Trial.

BACKGROUND: Rumination and overgeneral autobiographical memory are dysfunctional cognitions commonly found in older adults with depression. The theoretical underpinnings of mindfulness-based cognitive therapy (MBCT) address the ruminative tendencies and the non-specific retrieval of autobiographical memories. This study aims to examine the efficacy and cognitive mechanisms of MBCT in older adults with active depressive symptoms. METHODS: 57 older adults (mean age, 70 years) with normal cognition and mild to moderate depressive symptoms were randomly allocated to either the MBCT group or the active control group for 8 weeks. The MBCT group consisted of eight 2-hour weekly sessions and a 7-hour full-day retreat, with different themes for each class, guided mindfulness exercises, feedback and discussion, homework review, and psychoeducation. The active control group comprised a 1-hour physical exercise and a standardised health education of the specific theme with group discussion (eg fall prevention, chronic pain). Participants were assessed before and after the 8-week intervention for four outcome measures: the Hamilton Depression Rating Scale (HAMD), the Ruminative Response Scale (RRS), the Autobiographical Memory Test (AMT), and the Mindful Attention Awareness Scale (MAAS). RESULTS: There was a significant reduction in severity of depressive symptoms (HAMD score) in both the MBCT group (F(1, 27) = 35.9, p < 0.001, η2 = 0.57) and the active control group (F(1, 28) = 9.29, p < 0.01, η2 = 0.24), but only the MBCT group showed substantial improvements in autobiographical memory specificity (AMT score), rumination (RRS score), and mindfulness (MAAS score). CONCLUSION: Although both MBCT and active control programme decrease the severity of depressive symptoms in older adults, only MBCT improves AMS, rumination, and mindfulness. Our findings provide empirical support for the theoretical underpinnings of MBCT. Older adults with more severe depression and more severe dysfunctional cognition may benefit more from the specific therapeutic effects of MBCT.

Delta-9-tetrahydrocannabinol decreases masticatory muscle sensitization in female rats through peripheral cannabinoid receptor activation.

BACKGROUND: This study investigated whether intramuscular injection of delta-9-tetrahydrocannabinol (THC), by acting on peripheral cannabinoid (CB) receptors, could decrease nerve growth factor (NGF)-induced sensitization in female rat masseter muscle; a model which mimics the symptoms of myofascial temporomandibular disorders. METHODS: Immunohistochemistry was used to explore the peripheral expression of cannabinoid receptors in the masseter muscle while behavioural and electrophysiology experiments were employed to assess the functional effects of intramuscular injection of THC. RESULTS: It was found that CB1 and CB2 receptors are expressed by trigeminal ganglion neurons that innervate the masseter muscle and also on their peripheral endings. Their expression was greater in TRPV1-positive ganglion neurons. Three days after intramuscular injection of NGF, ganglion neuron expression of CB1 and CB2, but not TPRV1, was decreased. In behavioural experiments, intramuscular injection (10 µL) of THC (1 mg/mL) attenuated NGF-induced mechanical sensitization. No change in mechanical threshold was observed in the contralateral masseter muscles and no impairment of motor function was found after intramuscular injections of THC. In anaesthetized rats, the same concentration of THC increased the mechanical thresholds of masseter muscle mechanoreceptors. Co-administration of the CB1 antagonist AM251 blocked the effect of THC on masseter muscle mechanoreceptors while the CB2 antagonist AM630 had no effect. CONCLUSIONS: These results suggest that reduced inhibitory input from the peripheral cannabinoid system may contribute to NGF-induced local myofascial sensitization of mechanoreceptors. Peripheral application of THC may counter this effect by activating the CB1 receptors on masseter muscle mechanoreceptors to provide analgesic relief without central side effects. SIGNIFICANCE: Our results suggest THC could reduce masticatory muscle pain through activating peripheral CB1 receptors. Peripheral application of cannabinoids could be a novel approach to provide analgesic relief without central side effects.

Biofortification of rice with lysine using endogenous histones.

Rice is the most consumed cereal grain in the world, but deficient in the essential amino acid lysine. Therefore, people in developing countries with limited food diversity who rely on rice as their major food source may suffer from malnutrition. Biofortification of stable crops by genetic engineering provides a fast and sustainable method to solve this problem. In this study, two endogenous rice lysine-rich histone proteins, RLRH1 and RLRH2, were over-expressed in rice seeds to achieve lysine biofortification. Their protein sequences passed an allergic sequence-based homology test. Their accumulations in rice seeds were raised to a moderate level by the use of a modified rice glutelin 1 promoter with lowered expression strength to avoid the occurrence of physiological abnormalities like unfolded protein response. The expressed proteins were further targeted to protein storage vacuoles for stable storage using a glutelin 1 signal peptide. The lysine content in the transgenic rice seeds was enhanced by up to 35 %, while other essential amino acids remained balanced, meeting the nutritional standards of the World Health Organization. No obvious unfolded protein response was detected. Different degrees of chalkiness, however, were detected in the transgenic seeds, and were positively correlated with both the levels of accumulated protein and lysine enhancement. This study offered a solution to the lysine deficiency in rice, while at the same time addressing concerns about food safety and physiological abnormalities in biofortified crops.

Oral and topical boswellic acid attenuates mouse osteoarthritis.

OBJECTIVE: Boswellic acid is a plant-derived molecule with putative anti-inflammatory effects. This study was performed to determine whether oral or topical administration of boswellic acid can attenuate joint damage in a mouse model of osteoarthritis (OA). METHODS: Levels of boswellic acid were measured in the blood and synovium of mice treated with oral or topical boswellic acid. OA was generated by surgical destabilization of the medial meniscus (DMM). Therapy with oral or topical boswellic acid was initiated one day after surgery and continued for 12 weeks, when knees were harvested and scored histologically for degree of cartilage loss, osteophyte formation, and synovitis. Microdissected OA synovium was stimulated with IL-1ß or lipopolysaccharide (LPS) in the presence or absence of boswellic acid and cytokine production by quantitative polymerase chain reaction (PCR) or multiplex enzyme linked immunoabsorbant assay (ELISA). RESULTS: Topical treatment resulted in synovial concentrations of boswellic acid 2-6-fold higher than that measured in plasma. Cartilage loss was significantly reduced in mice treated with oral or topical boswellic acid compared with vehicle control (P < 0.01 for both oral and topical therapies). Likewise, treatment with either oral boswellic acid or boswellic acid ointment reduced of synovitis (P = 0.006 and 0.025, respectively) and osteophyte formation (P = 0.009 and 0.030, respectively). In vitro, boswellic acid was able to inhibit IL-1ß and TLR4 mediated induction of several inflammatory mediators from OA synovial explant tissue. CONCLUSIONS: Significant synovial concentration and therapeutic efficacy can be achieved with topical boswellic acid treatment. These findings suggest that boswellic acid has potential as a disease-modifying agent in OA.

Use of electroacupuncture to accelerate the antidepressant action of selective serotonin reuptake inhibitors: a single-blind, randomised, controlled study.

1. Patients treated with dense cranial electroacupuncture stimulation (DCEAS) had a significantly greater reduction in the 17-item Hamilton Rating Scale for Depression scores and clinically significant response to treatment than those having sham acupuncture (19.4% vs.8.8%). 2. Neither sham acupuncture nor DCEAS had effects on the platelet serotonin system. 3. In the early phase of selective serotonin reuptake inhibitor treatment for depressed patients, DCEAS could be used as an additional therapy. 4. Neurobiological mechanisms responsible for DCEAS effects warrant further investigation using neuroimaging.

Identification of the major chemical constituents and their metabolites in rat plasma and various organs after oral administration of effective Erxian Decoction (EXD) fraction by liquid chromatography-mass spectrometry.

A simple and specific LC-DAD-ESI-MS/MS method has been developed and applied for the primary investigation of the chemical constituents absorbed or metabolized in vivo, after the rat oral administration of Erxian Decoction (EXD), a Chinese medicine prescription for menopausal syndromes. Through the online ESI-MS(n) analysis, a total of 35 compounds have been identified or tentatively characterized from the seven tested samples, and 13 of them were unambiguously identified through a direct comparison of the retention time, UV spectra and MS(n) fragmentation patterns with the authentic ones. The results showed that 21 compounds were detected from rat plasma, 20 compounds were detected from rat kidneys and adrenal glands, 19 compounds were detected from rat ovaries, 12 compounds were found in rat intestines, nine compounds were identified from rat livers and nine compounds were detected from rat brains at certain time points after oral administration of the effective EXD fraction.

Preclinical assessment of the absorption, distribution, metabolism and excretion of GDC-0449 (2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide), an orally bioavailable systemic Hedgehog signalling pathway inhibitor.

GDC-0449 (2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide) is a potent, selective Hedgehog (Hh) signalling pathway inhibitor being developed for the treatment of various cancers. The in vivo clearance of GDC-0449 was estimated to be 23.0, 4.65, 0.338, and 19.3 ml min(-1) kg(-1) in mouse, rat, dog and monkeys, respectively. The volume of distribution ranged from 0.490 in rats to 1.68 l kg(-1) in mice. Oral bioavailability ranged from 13% in monkeys to 53% in dogs. Predicted human clearance using allometry was 0.096-0.649 ml min(-1) kg(-1) and the predicted volume of distribution was 0.766 l kg(-1). Protein binding was extensive with an unbound fraction less than or equal to 6%, and the blood-to-plasma partition ratio ranged from 0.6 to 0.8 in all species tested. GDC-0449 was metabolically stable in mouse, rat, dog and human hepatocytes and had a more rapid turnover in monkey hepatocytes. Proposed metabolites from exploratory metabolite identification in vitro (rat, dog and human liver microsomes) and in vivo (dog and rat urine) include three primary oxidative metabolites (M1-M3) and three sequential glucuronides (M4-M6). Oxidative metabolites identified in microsomes M1 and M3 were formed primarily by P4503A4/5 (M1) and P4502C9 (M3). GDC-0449 was not a potent inhibitor of P4501A2, P4502B6, P4502D6, and P4503A4/5 with IC50 estimates greater than 20 microM. K(i)'s estimated for P4502C8, P4502C9 and P4502C19 and were 6.0, 5.4 and 24 microM, respectively. An evaluation with Simcyp suggests that GDC-0449 has a low potential of inhibiting P4502C8 and P4502C9. Furthermore, GDC-0449 (15 microM) was not a potent P-glycoprotein/ABCB1 inhibitor in MDR1-MDCK cells. Overall, GDC-0449 has an attractive preclinical profile and is currently in Phase II clinical trials.

A novel mechanism: Erxian Decoction, a Chinese medicine formula, for relieving menopausal syndrome.

ETHNOPHARMACOLOGICAL RELEVANCE: Many clinical and experimental reports demonstrated that Erxian Decoction (EXD) was effective in relieving menopausal syndrome. AIM OF THE STUDY: The mechanisms of action of EXD were explored on the endocrine and antioxidant regimen. MATERIALS AND METHODS: Menopause causes a decline in both endocrine function and activities of antioxidant enzymes. In this study, 12-month-old female Sprague-Dawley-rats (SD-rats) with a low serum estradiol level were employed. Their endocrine functions after treatment with EXD were assessed by the determination of their serum estradiol level and ovarian mRNA levels of aromatase, which is a key enzyme for biosynthesis of estradiol. Meanwhile, superoxide dismutase-1 (SOD), catalase (CAT) and glutathione peroxidase (GPx-1) in the liver were also determined to assess the effect of EXD on the antioxidant regimen. RESULTS: Results revealed a significant elevation in serum estradiol level and the mRNA level of ovarian aromatase and liver CAT in the EXD-treated menopausal rat model. CONCLUSIONS: The results obtained from mRNA and estradiol level of the present investigation revealed that the EXD relieves the menopausal syndrome involved an increase of endocrine and antioxidant function through, at least, the activation of aromatase and CAT detoxifying pathways.

Probiotic supplementation in the first 6 months of life in at risk Asian infants--effects on eczema and atopic sensitization at the age of 1 year.

BACKGROUND: The role of probiotics in allergy prevention remains uncertain but has been shown in some studies to have a possible protective effect on eczema. OBJECTIVE: We aimed to assess the effect of probiotic supplementation in the first 6 months of life on eczema and allergic sensitization at 1 year of age in Asian infants at risk of allergic disease. METHODS: A double-blind, placebo-controlled randomized clinical trial involving 253 infants with a family history of allergic disease was carried out. Infants received at least 60 mL of commercially available cow's milk formula with or without probiotic supplementation [Bifidobacterium longum (BL999) 1 x 10(7) colony forming unit (CFU)/g and Lactobacillus rhamnosus (LPR) 2 x 10(7) CFU/g] daily for the first 6 months. Clinical evaluation was performed at 1, 3, 6 and 12 months of age, with serum total IgE measurement and skin prick tests conducted at the 12-month visit. The primary and secondary end-points were eczema and allergen sensitization, respectively. RESULTS: The incidence of eczema in the probiotic (22%) group was similar to that in the placebo group (25%) (P=0.53). The median Scoring Atopic Dermatitis score at 12 months was 17.10 (9.74) in the probiotic group and 11.60 (8.40) in the placebo group (P=0.17). The prevalence of allergen sensitization showed no difference (probiotic=24% vs. placebo=19%, P=0.26). The total IgE geometric mean (95% confidence interval) was 18.76 (12.54-24.98) kU/L in the probiotic group and 23.13 (16.01-30.24) kU/L in the placebo group (P=0.15). Atopic eczema (with sensitization) in the probiotic (7.3%) group was comparable to the placebo group (5.8%) (P=0.86). CONCLUSION: Early life administration of a cow's milk formula supplemented with probiotics showed no effect on prevention of eczema or allergen sensitization in the first year of life in Asian infants at risk of allergic disease. Further work is needed to determine whether timing of supplementation, dose and probiotic strain are important considerations.

Synergistic effects of dehydroepiandrosterone and fluoxetine on proliferation of progenitor cells in the dentate gyrus of the adult male rat.

The 5-HT re-uptake inhibitor (SSRI) fluoxetine and the adrenal hormone dehydroepiandrosterone (DHEA) both increase the proliferation of progenitor cells in the adult hippocampus and also have antidepressant activity. This paper explores the combined ability of fluoxetine and DHEA to affect this process in the dentate gyrus of adult rats. We show that DHEA can render an otherwise ineffective dose of fluoxetine (2.5 mg/kg) able to increase progenitor cell proliferation to the same extent as doses four times higher (10 mg/kg). This synergistic action does not appear to be mediated by alterations in brain-derived neurotrophic factor (BDNF) gene expression; or by TrkB, mineralocorticoid, glucocorticoid, or 5-HT (5HT1A) receptor expression in the dentate gyrus; or by altered levels of plasma corticosterone. In a second experiment, the synergism between DHEA and fluoxetine was replicated. Furthermore, flattening the diurnal rhythm of plasma corticosterone by implanting additional corticosterone pellets s.c. prevented the effect of fluoxetine on progenitor cell division. This was not overcome by simultaneous treatment with DHEA, despite the latter's reported anti-glucocorticoid actions. The cellular mechanism for the potentiating action of DHEA on the pro- proliferative effects of fluoxetine in the adult hippocampus remains to be revealed. Since altered neurogenesis has been linked to the onset or recovery from depression, one consequence of these results is to suggest DHEA as a useful adjunct therapy for depression.

CMOS-analogous wafer-scale nanotube-on-insulator approach for submicrometer devices and integrated circuits using aligned nanotubes.

Massive aligned carbon nanotubes hold great potential but also face significant integration/assembly challenges for future beyond-silicon nanoelectronics. We report a wafer-scale processing of aligned nanotube devices and integrated circuits, including progress on essential technological components such as wafer-scale synthesis of aligned nanotubes, wafer-scale transfer of nanotubes to silicon wafers, metallic nanotube removal and chemical doping, and defect-tolerant integrated nanotube circuits. We have achieved synthesis of massive aligned nanotubes on complete 4 in. quartz and sapphire substrates, which were then transferred to 4 in. Si/SiO(2) wafers. CMOS analogous fabrication was performed to yield transistors and circuits with features down to 0.5 mum, with high current density approximately 20 muA/mum and good on/off ratios. In addition, chemical doping has been used to build fully integrated complementary inverter with a gain approximately 5, and a defect-tolerant design has been employed for NAND and NOR gates. This full-wafer approach could serve as a critical foundation for future integrated nanotube circuits.

Synthesis of metal chalcogenide nanodot arrays using block copolymer-derived nanoreactors.

Soluble metal chalcogenide precursors are used to fabricate arrays of metal chalcogenide nanodots by spin-coating. Nanodots are formed after thermal decomposition of the precursors, which are collected in patterned nanowell arrays. These arrays are derived from block copolymer patterns and may consist of the polymer itself or result from etching to transfer the pattern to an inorganic substrate. Etching provides enhanced control over nanowell shape and the morphology of the resulting metal chalcogenide array.

A double-blind placebo-controlled randomized study of Chinese herbal medicine as complementary therapy for reduction of chemotherapy-induced toxicity.

BACKGROUND: Chinese herbal medicine (CHM) is a common complementary therapy used by patients with cancer for reduction of chemotherapy-induced toxic effects. This study applied the highest standard of clinical trial methodology to examine the role of CHM in reducing chemotherapy-induced toxicity, while maintaining a tailored approach to therapy. PATIENTS AND METHODS: Patients with early-stage breast or colon cancer who required postoperative adjuvant chemotherapy were eligible for the study. Enrolled patients were randomly assigned to one of three Chinese herbalists who evaluated and prescribed a combination of single-item packaged herbal extract granules. Patients received either CHM or placebo packages with a corresponding serial number. The placebo package contained nontherapeutic herbs with an artificial smell and taste similar to a typical herbal tea. The primary end points were hematologic and non-hematologic toxicity according to the National Cancer Institute Common Toxicity Criteria Version 2. RESULTS: One hundred and twenty patients were accrued at the time of premature study termination. Patient characteristics of the two groups were similar. The incidence of grade 3/4 anemia, leukopenia, neutropenia, and thrombocytopenia for the CHM and placebo groups were 5.4%, 47.3%, 52.7%, and 1.8% and 1.8%, 32.2%, 44.7%, and 3.6%, respectively (P = 0.27, 0.37, 0.63, and 0.13, respectively). Incidence of grade 2 nausea was the only non-hematologic toxicity that was significantly reduced in the CHM group (14.6% versus 35.7%, P = 0.04). CONCLUSIONS: Traditional CHM does not reduce the hematologic toxicity associated with chemotherapy. CHM, however, does have a significant impact on control of nausea.

Weekly fluorouracil at 425 mg/m(2) plus low-dose folinic acid for 24 weeks as adjuvant treatment for colorectal cancer: assessment of toxicity and delivery.

AIMS: To assess the toxicity and dose delivery of weekly bolus 5-fluorouracil (5-FU) at 425 mg/m(2) plus low-dose folinic acid (FA) for 24 weeks as adjuvant treatment for colorectal cancer. MATERIALS AND METHODS: Data were collected on toxicity and dose reductions, stoppages, delays and intensity from 100 consecutive patients receiving this adjuvant regimen after curative surgery. RESULTS: There were 53 men and 47 women (median age: 64 and 65 years, respectively); 77 patients with colon cancer and 23 with cancer of the rectum; 34 patients with Dukes' stage B and 66 with Dukes' stage C. Thirty-seven patients experienced at least one grade 3 or 4 toxicity, mainly diarrhoea (20 patients) or fatigue (14 patients). Only one grade 4 toxicity was noted (diarrhoea). In multivariate analysis, increased grade 3 and 4 toxicity was significantly associated with female gender (P = 0.001) and age >65 years (P = 0.046). Forty patients completed the 24 cycles without dose reduction or delay. Forty-one patients required at least one dose reduction. The median 'conventional' dose intensity (DI), calculated from the first cycle to the last, was 408 mg/m(2)/week (96%). The median DI over 24 weeks was 387 mg/m(2)/week (91%). A higher median 24-week DI was delivered to men (407 mg/m(2)/week, 96%) than women (361 mg/m(2)/ week, 85%; P = 0.009). Women older than 65 years showed a significantly reduced median DI over 24 weeks (347 mg/ m(2)/week, 82%) compared with men aged 65 years or younger (407 mg/m(2)/week, 96%; P = 0.049) and men older than 65 years (425 mg/m(2)/week, 100%; P = 0.001), although the difference against women aged 65 years or younger (377 mg/ m(2)/week, 89%) was not statistically significant (P = 0.09). CONCLUSION: This regimen has shown what might be considered high rates of grade 3 and 4 toxicity for an adjuvant treatment, although the delivered DI was acceptable. Caution is urged in the treatment of elderly female patients who have statistically higher rates of grade 3 and 4 toxicity and lower DI.

Protective effects of isohelenin, an inhibitor of nuclear factor kappaB, in endotoxic shock in rats.

Recent in vitro studies have shown that isohelenin, a sesquiterpene lactone, inhibits the NF-kappaB pathway. This study examines the effect of isohelenin in endotoxic shock induced by administration of Escherichia coli endotoxin in male Wistar rats. A group of rats received isohelenin (2 mg/kg intraperitoneally) 15 min before endotoxin. In vehicle-treated rats, administration of endotoxin caused severe hypotension, which was associated with a marked hyporeactivity to norepinephrine and acetylcholine in ex vivo aortas. Elevated levels of plasma nitrate/nitrite, metabolites of nitric oxide (NO), were also found. These inflammatory events were preceded by cytosolic degradation of inhibitor-kappaBalpha (IkappaBalpha) and activation of nuclear factor-kappaB (NF-kappaB) in the lung within 15 min of endotoxin administration. Treatment with isohelenin resulted in hemodynamic improvement and reduced plasma levels of NO metabolites. Nuclear translocation of NF-kappaB was inhibited by isohelenin treatment in the lung, whereas degradation of IkappaBalpha was unchanged. In a separate set of experiments, treatment with isohelenin significantly improved survival in mice challenged with endotoxin. We conclude that isohelenin exerts beneficial therapeutic effects during endotoxic shock through inhibition of NF-kappaB.

Curcumin, a medicinal herbal compound capable of inducing the heat shock response.

OBJECTIVE: There is interest in developing pharmacologic inducers of the heat shock response as a means to confer cytoprotection in the clinical setting. We propose that a potential strategy for screening novel pharmacologic inducers of the heat shock response is to examine known inhibitors of the transcription factor nuclear factor-kappaB. Curcumin, derived from the tropical herb Curcuma longa, is a recently described inhibitor of nuclear factor-kappaB and is widely used in Eastern medicinal practices. We tested the hypothesis that curcumin can induce expression of heat shock protein 70. DESIGN: Experimental. SETTING: University laboratory. SUBJECTS: HeLa cells. INTERVENTIONS: HeLa cells were exposed to varying concentrations of curcumin and analyzed for expression of heat shock protein 70 by Western blot. MEASUREMENTS AND MAIN RESULTS: Activation of the transcription factor, heat shock factor-1, was analyzed by electromobility shift assays. Curcumin-mediated inhibition of nuclear factor-kappaB activation was measured by transiently transfecting cells with a nuclear factor-kappaB luciferase reporter plasmid. The role of heat shock factor-1 in curcumin-mediated expression of heat shock protein 70 was tested in embryonic fibroblasts derived from heat shock factor-1 knockout mice. Induction of the heat shock response was quantified by transiently transfecting cells with a heat shock protein 70 promoter-luciferase reporter plasmid. Cell viability was measured by using the tetrazolium dye 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay. Curcumin induced expression of heat shock protein 70, the major inducible heat shock protein in cells undergoing the heat shock response, in a dose-dependent and time-dependent manner. Curcumin induced specific nuclear translocation and activation of heat shock factor-1. Curcumin-mediated expression of heat shock protein 70 was reduced substantially in fibroblasts having genetic ablation of heat shock factor-1. The extent of induction of the heat shock response correlated, in part, with cellular toxicity. CONCLUSIONS: Curcumin, a widely used medicinal compound, induces the heat shock response in vitro as measured by expression of heat shock protein 70. The mechanism of heat shock protein 70 induction depends on activation of heat shock factor-1. Examining known inhibitors of nuclear factor-kappaB for their ability to induce heat shock protein 70 may be a valid screening method to discover novel pharmacologic inducers of the heat shock response.