The antiatherogenic effect of allicin: possible mode of action.

OBJECTIVE: Garlic (Allium sativum) has been suggested to affect several cardiovascular risk factors. Its antiatherosclerotic properties are mainly attributed to allicin that is produced upon crushing of the garlic clove. Most previous studies used various garlic preparations in which allicin levels were not well defined. In the present study, we evaluated the effects of pure allicin on atherogenesis in experimental mouse models. METHODS AND RESULTS: Daily dietary supplement of allicin, 9 mg/kg body weight, reduced the atherosclerotic plaque area by 68.9 and 56.8% in apolipoprotein E-deficient and low-density lipoprotein (LDL) receptor knockout mice, respectively, as compared with control mice. LDL isolated from allicin-treated groups was more resistant to CuSO(4)-induced oxidation ex vivo than LDL isolated from control mice. Incubation of mouse plasma with (3)H-labeled allicin showed binding of allicin to lipoproteins. By using electron spin resonance, we demonstrated reduced Cu(2+) binding to LDL following allicin treatment. LDL treatment with allicin significantly inhibited both native LDL and oxidized LDL degradation by isolated mouse macrophages. CONCLUSIONS: By using a pure allicin preparation, we were able to show that allicin may affect atherosclerosis not only by acting as an antioxidant, but also by other mechanisms, such as lipoprotein modification and inhibition of LDL uptake and degradation by macrophages.     

Amelioration of Child Depression Through Behavioral Parent Training: A Preliminary Study

Child depression is an impairing condition for which tested treatments have shown relatively modest mean effects. One possible explanation is that the treatments have generally adopted an individual child focus, without addressing the dysfunctional parent–child interactions that often accompany child depression. The present study provides preliminary evidence bearing on this hypothesis, using data from a treatment outcome study in which clinically referred children with a depression diagnosis could receive individual cognitive behavioral therapy (CBT) focusing on the depression or behavioral parent training (BPT) focusing on comorbid conduct problems. Among children in the study who met criteria for Diagnostic and Statistical Manual of Mental Disorders (4th ed.) depressive disorders, we identified two groups, matched on gender and age: 15 who received only CBT focused on child depression and 15 who received only BPT focused on child conduct problems. Children were 7 to 13, 20 of whom were male, and race included Caucasian (17), Latino (5), African American (2), and multirace (6). Measures assessed depressive diagnoses and symptoms, as well as parenting stress. Analyses focused on whether BPT alone might lead to reduced depression, and if so how that reduction would compare to the depression reduction achieved through CBT that focused on depression. Both groups showed significant reductions from pre- to post-treatment in depressive diagnoses and depression symptoms, and there were no BPT versus CBT group differences at post-treatment. BPT that focuses on child conduct problems, with no emphasis on depression treatment, may produce significant depression reduction in comorbid children who meet criteria for depressive disorders.     

Combining individual cognitive behaviour therapy and caregiver-child sessions for childhood depression: an open trial

The objective was to obtain preliminary evidence on the feasibility and efficacy of combining individual cognitive behavior therapy (CBT) with complimentary caregiver-child sessions for depressed youths. Fifteen children participated in an open clinical trial. Treatment included 16 CBT sessions combined with seven caregiver/caregiver-child sessions over 12 weeks. Data were collected at pre-, mid-, and post-treatment and at one- and six-month follow-ups. Significant decreases in depressive symptoms were apparent, with the majority showing clinically meaningful improvement. Benchmarked against the literature, the combination equaled or outperformed CBT in other studies and was superior to control conditions. Mother and teacher reports of child functioning significantly improved, providing social validation of the effects. Mothers reported improved caregiver-child relationships and less parenting stress. Children did not report acute improvements in relations with their caregivers. However, when a father participated, improved father-child relations were reported in the follow-up period. Younger age and lower pretreatment severity predicted greater symptom change. The positive treatment effects provide support for the combined intervention and suggest a further research focus on the effects of caregiver involvement in the treatment of depressed youths.     

Novel prodrugs of tegafur that display improved anticancer activity and antiangiogenic properties

New and more potent prodrugs of the 5-fluorouracyl family derived by hydroxymethylation or acyloxymethylation of 5-fluoro-1-(tetrahydro-2-furanyl)-2,4(1H,3H)-pyrimidinedione (tegafur, 1) are described. The anticancer activity of the butyroyloxymethyl-tegafur derivative 3 and not that of tegafur was attenuated by the antioxidant N-acetylcysteine, suggesting that the increased activity of the prodrug is in part mediated by an increase of reactive oxygen species. Compound 3 in an in vitro matrigel assay was found to be a more potent antiangiogenic agent than tegafur. In vivo 3 was significantly more potent than tegafur in inhibiting 4T1 breast carcinoma lung metastases and growth of HT-29 human colon carcinoma tumors in a mouse xenograft. In summary, the multifunctional prodrugs of tegafur display selectivity toward cancer cells, antiangiogenic activity, and anticancer activities in vitro and in vivo, superior to those of tegafur. 5-fluoro-1-(tetrahydro-2-furanyl)-2,4(1 H,3 H)-pyrimidinedione (tegafur, 1), the oral prodrug of 5-FU, has been widely used for treatment of gastrointestinal malignancies with modest efficacy. The aim of this study was to develop and characterize new and more potent prodrugs of the 5-FU family derived by hydroxymethylation or acyloxymethylation of tegafur. Comparison between the effect of tegafur and the new prodrugs on the viability of a variety of cancer cell lines showed that the IC50 and IC90 values of the novel prodrugs were 5-10-fold lower than those of tegafur. While significant differences between the IC50 values of tegafur were observed between the sensitive HT-29 and the resistant LS-1034 colon cancer cell lines, the prodrugs affected them to a similar degree, suggesting that they overcame drug resistance. The increased potency of the prodrugs could be attributed to the antiproliferative contribution imparted by formaldehyde and butyric acid, released upon metabolic degradation. The anticancer activity of the butyroyloxymethyl-tegafur derivative 3 and not that of tegafur was attenuated by the antioxidant N-acetylcysteine, suggesting that the increased activity of the prodrug is in part mediated by an increase of reactive oxygen species. Compound 3 in an in vitro matrigel assay was found to be a more potent antiangiogenic agent than tegafur. In vivo 3 was significantly more potent than tegafur in inhibiting 4T1 breast carcinoma lung metastases and growth of HT-29 human colon carcinoma tumors in a mouse xenograft. In summary, the multifunctional prodrugs of tegafur display selectivity toward cancer cells, antiangiogenic activity and anticancer activities in vitro and in vivo, superior to those of tegafur.     

‘It is nothing more than a senior moment’: the moderating role of subjective age in the effect of change in memory on self-rated memory

Objective: The association between memory performance and self-rated memory is yet to be understood. More specifically, little is known about the factors that lie at the base of self-evaluations of memory in relation to actual changes in memory. In this study, we suggest that subjective age modifies the effect of objective change in memory on self-rated memory.

Method: We used two waves of the Health and Retirement Study (N = 4624) to examine whether subjective age moderates the effect of experienced changes in memory between T1 and T2 on self-rated memory at T2.

Results: Our results suggest that subjective age is a significant moderator of the effect of change in memory on self-rated memory. The effect is weaker among those with younger subjective age, and stronger for those with older subjective age.

Conclusion: While preserving a young subjective age is usually considered an adaptive strategy, it also has potential negative effects, masking changes in memory performance.     

Motor skills,cognition, and work performance of people with severe mental illness

Purpose: Employment offers many benefits to people with mental illness, yet their employment rate is much lower than that of the general population. We investigated the effect of work-related motor skills, neurocognition, and job attitudes on the work performance of people with mental illness, comparing those working in sheltered workshops, with controls working in similar jobs.

Methods: Twenty-nine adults with severe mental illness and 27 controls matched by gender and age were enrolled into the study using convenience sampling. They were assessed for gross and fine motor hand functioning, job attitudes, work performance, and cognition.

Results: People with mental illness scored lower on work performance, cognitive functioning, and hand dexterity while sitting and working with tools. They were assigned lower job loads than were controls, and perceived the physical environment at work as more constraining than did controls. Assembling motor skills significantly explained the work performance of people with mental illness.

Conclusions: The results expand our understanding of the complexities involved in the employment of people with severe mental illness, and point to new paths for improving vocational outcomes of people with severe mental illness, taking into account their motor skills and job attitudes.

• Implications for rehabilitation

• Therapists should be aware that employed people with severe mental illness may have various unmet needs, affecting their work performance and experience of stress.

• This study results demonstrate importance of motor skills and perception of the work environment for the promotion of vocational outcomes among individuals with severe mental illness.

• Employment of people with severe mental illness should be viewed from holistic perspective as with general population, rather than focused on traditionally illness-related factors.

     

Inhibition of carcinogenesis in transgenic mouse models over-expressing 15-lipoxygenase in the vascular wall under the control of murine preproendothelin-1 promoter

Oxygenases are a family of enzymes that dioxygenate unsaturated fatty acids, thus initiating membrane oxidation and signaling molecule synthesis. The lipoxygenases (LOs), a family of lipid-peroxidizing enzymes that induce structural and metabolic changes in the cell in a number of pathophysiological conditions, belong to the oxygenases family. This class of enzymes has several subgroups, named 5-, 8-, 12- and 15-LOs, and these LO-isoforms are capable of oxygenating arachidonic and linoleic acid. 15-LOs were reported to play an inhibitory role in tumor angiogenesis and, consequently, they slow down carcinogenesis. It has been suggested that its anti-carcinogenic effect is conferred by promoting cell differentiation and apoptosis. Using transgenic mice that over-express 15-LO-1 in endothelial cells under the regulation of the murine preproendothelin-1 promoter, we studied its effect on tumor and metastasis growth. We found that 15-LO-1 inhibited tumor and metastasis growth in the transgenic mice in two different models of cancer (mammary gland and Lewis lung carcinoma). This inhibition was concomitant with a higher number of apoptotic cells in the metastases of the transgenic mice and with a complicated network of multiple small blood vessels. This finding targets 15-LO as a new candidate in the treatment of carcinogenesis.     

Effect of a social skills training group on everyday activities of children with attention-deficit-hyperactivity disorder

This preliminary study compared the daily living skills of children with and without attention-deficit-hyperactivity disorder (ADHD), and the influence of a social skills training group on these skills. Twenty-seven children with ADHD (2 females, 25 males; age range 5 to 8y, mean 6y 6mo, SD 10mo), and 24 children without ADHD (8 females, 16 males; age range 5 to 8y, mean 6y 11mo, SD 10mo) performed the Assessment of Motor and Process Skills (AMPS). Fourteen of the children with ADHD used medication daily. Nine of the total group with ADHD were randomly selected to attend group treatment which focused on social skills training, through meaningful occupations (e.g. art, games, cooking). Children were evaluated at the beginning of group treatment and after 10 sessions. Ten children without ADHD were evaluated at similar intervals. Children with ADHD initially achieved significantly lower scores on the AMPS in all process skills (p<0.001) and in the coordination motor subtest (p<0.005) than children without ADHD. Children with ADHD significantly improved from the first to the second evaluation and no longer differed from the children without ADHD after treatment (p<0.008). The results emphasize the need for a focus upon occupation in assessment and treatment of children with ADHD.     

Chimeric beta2 microglobulin/CD3zeta polypeptides expressed in T cells convert MHC class I peptide ligands into T cell activation receptors: a potential tool for specific targeting of pathogenic CD8(+) T cells

CD8(+) T cells are key mediators of transplant rejection and graft-versus-host disease and contribute to the pathogenesis of autoimmune diseases. We tested whether TCR ligands can be converted into T cell activation receptors, redirecting genetically modified T cells at pathogenic CD8(+) T cells. For this purpose we exploited the ability of the non-polymorphic beta(2) microglobulin light chain to pair with all MHC class I heavy chains. In this report we describe the design and expression in a T cell hybridoma of two modalities of beta(2) microglobulin polypeptides, fused with the transmembrane and intracellular portion of CD3zeta chain. In the absence of a particular antigenic peptide, the chimeric product associates with different endogenous MHC class I heavy chains and triggers T cell activation upon heavy chain cross-linking. When an antigenic peptide is covalently attached to the N-terminus of the chimeric polypeptide, transfectants express high level of surface peptide-class I complexes and respond to antibodies and target T cells in a peptide-specific manner. Our results provide the basis for a universal genetic approach aimed at antigen-specific immunotargeting of pathogenic CD8(+) T cells.