Therapist affiliation and hostility in cognitive-behavioral therapy with and without motivational interviewing for severe generalized anxiety disorder.

OBJECTIVE: Although therapist supportive, rather than directive, strategies have been particularly indicated during client resistance, little systematic research has examined how therapists responsively navigate resistance in different therapy approaches and how this responsiveness is related to outcome. METHOD: In the context of disagreement episodes in cognitive-behavioral therapy (CBT) for generalized anxiety disorder (GAD; Westra, H. A., Constantino, M. J., & Antony, M. M. Integrating motivational interviewing with cognitive-behavioral therapy for severe generalized anxiety disorder: An allegiance-controlled randomized clinical trial. Journal of Consulting and Clinical Psychology, 84(9), 768-782. https://doi.org/10.1037/ccp0000098, 2016), the present study examined (1) the degree to which therapist management of resistance differed between therapists trained in CBT integrated with motivational interviewing (MI-CBT; i.e., training centered on the responsive management of resistance) and therapists trained in CBT-alone, and (2) the impact of specific therapist behaviors during disagreement on client worry outcomes immediately posttreatment and 1-year posttreatment. Episodes of disagreement were rated used the Structural Analysis of Social Behavior (Benjamin, L. S. Structural analysis of social behavior. Psychological Review, 81(5), 392-425. https://doi.org/10.1037/h0037024, 1974). RESULTS: Therapists trained in MI-CBT were found to exhibit significantly more affiliative and fewer hostile behaviors during disagreement compared to those trained in CBT-alone; both of these, in turn, were found to mediate client 1-year posttreatment outcomes, such that increased affiliation during disagreement was associated with improved outcomes. CONCLUSION: This study highlights the value of training therapists in the responsive detection and management of resistance, as well as the systematic integration of MI into CBT.

Oxidized phosphatidylcholines trigger ferroptosis in cardiomyocytes during ischemia-reperfusion injury.

Myocardial ischemia-reperfusion (I/R) injury increases the generation of oxidized phosphatidylcholines (OxPCs), which results in cell death. However, the mechanism by which OxPCs mediate cell death and cardiac dysfunction is largely unknown. The aim of this study was to determine the mechanisms by which OxPC triggers cardiomyocyte cell death during reperfusion injury. Adult rat ventricular cardiomyocytes were treated with increasing concentrations of various purified fragmented OxPCs. Cardiomyocyte viability, bioenergetic response, and calcium transients were determined in the presence of OxPCs. Five different fragmented OxPCs resulted in a decrease in cell viability, with 1-palmitoyl-2-(5'-oxo-valeroyl)-sn-glycero-3-phosphocholine (POVPC) and 1-palmitoyl-2-(9'-oxo-nonanoyl)-sn-glycero-3-phosphocholine (PONPC) having the most potent cardiotoxic effect in both a concentration and time dependent manner (P < 0.05). POVPC and PONPC also caused a significant decrease in Ca2+ transients and net contraction in isolated cardiomyocytes compared to vehicle treated control cells (P < 0.05). PONPC depressed maximal respiration rate (P < 0.01; 54%) and spare respiratory capacity (P < 0.01; 54.5%). Notably, neither caspase 3 activation or TUNEL staining was observed in cells treated with either POVPC or PONPC. Further, cardiac myocytes treated with OxPCs were indistinguishable from vehicle-treated control cells with respect to nuclear high-mobility group box protein 1 (HMGBP1) activity. However, glutathione peroxidase 4 activity was markedly suppressed in cardiomyocytes treated with POVPC and PONPC coincident with increased ferroptosis. Importantly, cell death induced by OxPCs could be suppressed by E06 Ab, directed against OxPCs or by ferrostatin-1, which bound the sn-2 aldehyde of POVPC during I/R. The findings of the present study demonstrate that oxidation of phosphatidylcholines during I/R generate bioactive phospholipid intermediates that disrupt mitochondrial bioenergetics and calcium transients and provoke wide spread cell death through ferroptosis. Neutralization of OxPC with E06 or with ferrostatin-1 prevents cell death during reperfusion. Our study demonstrates a novel signaling pathway that operationally links generation of OxPC during cardiac I/R to ferroptosis. Interventions designed to target OxPCs may prove beneficial in mitigating ferroptosis during I/R injury in individuals with ischemic heart disease.NEW & NOTEWORTHY Oxidized phosphatidylcholines (OxPC) generated during reperfusion injury are potent inducers of cardiomyocyte death. Our studies have shown that OxPCs exert this effect through a ferroptotic process that can be attenuated. A better understanding of the OxPC cell death pathway can prove a novel strategy for prevention of cell death during myocardial reperfusion injury.

Exercise-induced increases in the expression and activity of cardiac sarcoplasmic reticulum calcium ATPase 2 is attenuated in AMPKα2 kinase-dead mice.

Exercise enhances cardiac sarcoplasmic reticulum Ca2+-ATPase 2a (SERCA2a) function through unknown mechanisms. The present study tested the hypothesis that the positive effects of exercise on SERCA2a expression and function in the left ventricle is dependent on adenosine-monophosphate-activated protein kinase (AMPK) α2 function. AMPKα2 kinase-dead (KD) transgenic mice, which overexpress inactivated AMPKα2 subunit, and wild-type C57Bl/6 (WT) mice were randomized into sedentary groups or groups with access to running wheels. After 5 months, exercised KD mice exhibited shortened deceleration time compared with sedentary KD mice. In left ventricular tissue, the ratio of phosphorylated AMPKαThr172:total AMPKα was 65% lower (P < 0.05) in KD mice compared with WT mice. The left ventricle of KD mice had 37% lower levels of SERCA2a compared with WT mice. Although exercise increased SERCA2a protein levels in WT mice by 53%, this response of exercise was abolished in exercised KD mice. Exercise training reduced total phospholamban protein content by 23% in both the WT and KD mice but remained 20% higher overall in KD mice. Collectively, these data suggest that AMPKα influences SERCA2a and phospholamban protein content in the sedentary and exercised heart, and that exercise-induced changes in SERCA2a protein are dependent on AMPKα function.

The impact of resistance on empathy in CBT for generalized anxiety disorder.

OBJECTIVE: Client resistance has been shown to relate to poorer therapy outcomes, thus making it important to better understand the mechanisms underlying this association. Given observational research suggesting that therapist empathy decreases during moments of resistance, the present study examined client-rated therapist empathy as a potential mediator of the resistance-outcome association. METHOD: Participants included 44 therapist-client dyads receiving cognitive-behavioral therapy for generalized anxiety disorder. Trained observers rated an early therapy session for the level of client resistance, and clients completed a corresponding postsession measure of therapist empathy. Posttreatment outcome was measured via client-rated worry severity. RESULTS: Higher client resistance was significantly associated with poorer treatment outcome and lower client postsession ratings of therapist empathy; however, therapist empathy was not observed to mediate the relationship between resistance and treatment outcomes. CONCLUSIONS: As empathy did not mediate the association between resistance and outcome, future research is needed to uncover other potential mechanisms of this association. However, the current results underscore an important link between resistance and client perceived therapist empathy. As empathy has been shown to relate positively to therapy outcomes, our result highlights the need to enhance therapist in-session responsivity to resistance in psychotherapy research and training.

Therapist empathy, homework compliance, and outcome in cognitive behavioral therapy for generalized anxiety disorder: partitioning within- and between-therapist effects.

Although client-perceived therapist empathy relates to positive therapy outcomes, including in cognitive behavioral therapy (CBT), little is known about how empathy exerts its ameliorative effect. One possible way is by promoting clients' subsequent homework compliance, a variable that also predicts positive outcomes in CBT. The present study sought to investigate simultaneously, in the context of 43 therapist-client dyads receiving 15 sessions of CBT for generalized anxiety disorder, (1) the association of early client-perceived therapist empathy (averaged over sessions 1, 3, 5) with mid-treatment client homework compliance (averaged over sessions 6, 8, 10); (2) the association of mid-treatment homework compliance on client posttreatment worry severity; and (3) the indirect effect of early perceived therapist empathy on posttreatment worry through mid-treatment homework compliance. Given that clients were nested within therapists, we examined both within- and between-therapist differences in clients' ratings of therapist empathy and homework compliance, and tested both of these indices as predictors of the relevant dependent variables in a multilevel model. At the within-therapist level (i.e., differences between clients within a given therapist's caseload), greater early empathy was associated with greater mid-treatment homework compliance. At the between-therapist level (i.e., differences between therapists across all of their cases), greater between-therapist homework compliance was related to lower posttreatment worry. Finally, homework compliance was not found to mediate the relationship between empathy and posttreatment outcome. The results underscore the importance of parsing client and therapist effects, and are discussed with regard to their training and research implications.

Disentangling the impact of resistance and ambivalence on therapy outcomes in cognitive behavioural therapy for generalized anxiety disorder.

Resistance and ambivalence about change are increasingly recognized as important determinants of treatment outcomes. Moreover, resistance and ambivalence are thought to be theoretically related in that clients who are more ambivalent about change are more likely to demonstrate resistance to the process and tasks of treatment. In the context of cognitive behavioural therapy (CBT) for generalized anxiety disorder, the present study simultaneously examined early resistance and ambivalence using two observer-based coding systems in order to determine their inter-relationship and, importantly, to investigate their relative contributions to outcome. Resistance was also coded during mid-treatment in order to investigate possible mediation pathways. Early ambivalence (clients' arguments against change or counter-change talk) was found to be no longer related to outcomes when early resistance was taken into account, suggesting that disharmony in the therapeutic relationship is more important to outcomes than ambivalence per se. Moreover, mid-treatment resistance partially mediated the relationship between early resistance and post-treatment worry severity. That is, higher early opposition to therapist direction is related to poorer outcomes, in part because it is associated with greater resistance during the working phase of CBT. The findings underscore the critical need for therapists to be sensitive to identifying resistance early and throughout treatment.

Therapist awareness of client resistance in cognitive-behavioral therapy for generalized anxiety disorder.

Clients' resistance relates negatively to their retention and outcomes in psychotherapy; thus, it has been increasingly identified as a key process marker in both research and practice. This study compared therapists' postsession ratings of resistance with those of trained observers in the context of 40 therapist-client dyads receiving 15 sessions of cognitive-behavioral therapy for generalized anxiety disorder. Therapist and observer ratings were then examined as correlates of proximal (therapeutic alliance quality and homework compliance) and distal (posttreatment worry severity) outcomes. Although there was reasonable concordance between rater perspectives, observer ratings were highly and consistently related to both proximal and distal outcomes, while therapist ratings were not. These findings underscore the need to enhance therapists' proficiency in identifying important and often covert in-session clinical phenomena such as the cues reflecting resistance and noncollaboration.

Beneficial Effects of Dietary Flaxseed on Non-Alcoholic Fatty Liver Disease.

Non-alcoholic fatty liver disease (NAFLD), a significant cause of chronic liver disease, presents a considerable public health concern. Despite this, there is currently no treatment available. This study aimed to investigate dietary flaxseed in the JCR:LA-corpulent rat strain model of NAFLD. Both obese male and female rats were studied along with their lean counterparts after 12 weeks of ingestion of a control diet, or control diet with flaxseed, or high fat, high sucrose (HFHS), or HFHS plus flaxseed. Obese rats showed higher liver weight and increased levels of cholesterol, triglyceride, and saturated fatty acid, which were further elevated in rats on the HFHS diet. The HFHS diet induced a significant two-fold elevation in the plasma levels of both aspartate aminotransferase and alanine aminotransferase in the obese male and female rats. Including flaxseed in the HFHS diet significantly lowered liver weight, depressed the plasma levels of both enzymes in the obese male rats, and reduced hepatic cholesterol and triglyceride content as well as improving the fatty acid profile. In summary, including flaxseed in the diet of male and female obese rats led to an improved lipid composition in the liver and significantly reduced biomarkers of tissue injury despite consuming a HFHS chow.

Regulation of Cardiac Fibroblast GLS1 Expression by Scleraxis.

Fibrosis is an energy-intensive process requiring the activation of fibroblasts to myofibroblasts, resulting in the increased synthesis of extracellular matrix proteins. Little is known about the transcriptional control of energy metabolism in cardiac fibroblast activation, but glutaminolysis has been implicated in liver and lung fibrosis. Here we explored how pro-fibrotic TGFß and its effector scleraxis, which drive cardiac fibroblast activation, regulate genes involved in glutaminolysis, particularly the rate-limiting enzyme glutaminase (GLS1). The GLS1 inhibitor CB-839 attenuated TGFß-induced fibroblast activation. Cardiac fibroblast activation to myofibroblasts by scleraxis overexpression increased glutaminolysis gene expression, including GLS1, while cardiac fibroblasts from scleraxis-null mice showed reduced expression. TGFß induced GLS1 expression and increased intracellular glutamine and glutamate levels, indicative of increased glutaminolysis, but in scleraxis knockout cells, these measures were attenuated, and the response to TGFß was lost. The knockdown of scleraxis in activated cardiac fibroblasts reduced GLS1 expression by 75%. Scleraxis transactivated the human GLS1 promoter in luciferase reporter assays, and this effect was dependent on a key scleraxis-binding E-box motif. These results implicate scleraxis-mediated GLS1 expression as a key regulator of glutaminolysis in cardiac fibroblast activation, and blocking scleraxis in this process may provide a means of starving fibroblasts of the energy required for fibrosis.

Testing a deliberate practice workshop for developing appropriate responsivity to resistance markers.

Deliberate practice (DP) is an emerging training method for improving individual performance that may be worth adapting and testing for applicability to groups, given the prevalence of group training for continuing education. This study compared an adapted DP workshop to the same traditional, non-DP workshop for managing ambivalence and resistance. The same presenter delivered the workshops to 88 randomly assigned community psychotherapists. The DP workshop involved repeated interaction with multiple recreations of resistance, with consistent group feedback especially on ideal expert performance. The control workshop was more didactic, with fewer opportunities for practice and feedback. We assessed video vignette performance and coded 20-min interviews with ambivalent interviewees from the community. Both workshops produced equivalent trainee satisfaction and significant increases in self-reported skills. However, the DP versus control group demonstrated better observer-rated skill on all performance measures postworkshop. Although skills declined to 4-month retest in both groups, the DP trainees retained their relative advantage over traditional workshop trainees. Moreover, at the 4-month follow-up, DP versus control trainees were rated as more empathic by community interviewees and self-reported practicing the skills at higher rates. These findings support the continued investigation of DP as a means for improving therapist skill in continuing education workshops. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Muscle-specific sirtuin 3 overexpression does not attenuate the pathological effects of high-fat/high-sucrose feeding but does enhance cardiac SERCA2a activity.

Obesity, type 2 diabetes, and heart disease are linked to an unhealthy diet. Sarco(endo)plasmic reticulum calcium (Ca2+ ) ATPase 2a (SERCA2a) controls cardiac function by transporting Ca2+ in cardiomyocytes. SERCA2a is altered by diet and acetylation, independently; however, it is unknown if diet alters cardiac SERCA2a acetylation. Sirtuin (SIRT) 3 is an enzyme that might preserve health under conditions of macronutrient excess by modulating metabolism via regulating deacetylation of target proteins. Our objectives were to determine if muscle-specific SIRT3 overexpression attenuates the pathological effects of high fat-high sucrose (HFHS) feeding and if HFHS feeding alters cardiac SERCA2a acetylation. We also determined if SIRT3 alters cardiac SERCA2a acetylation and regulates cardiac SERCA2a activity. C57BL/6J wild-type (WT) mice and MCK-mSIRT3-M1-Flag transgenic (SIRT3TG ) mice, overexpressing SIRT3 in cardiac and skeletal muscle, were fed a standard-diet or a HFHS-diet for 4 months. SIRT3TG and WT mice developed obesity, glucose intolerance, cardiac dysfunction, and pathological cardiac remodeling after 4 months of HFHS feeding, indicating muscle-specific SIRT3 overexpression does not attenuate the pathological effects of HFHS-feeding. Overall cardiac lysine acetylation was increased by 63% in HFHS-fed mice (p = 0.022), though HFHS feeding did not alter cardiac SERCA2a acetylation. Cardiac SERCA2a acetylation was not altered by SIRT3 overexpression, whereas SERCA2a Vmax was 21% higher in SIRT3TG (p = 0.039) than WT mice. This suggests that SIRT3 overexpression enhanced cardiac SERCA2a activity without direct SERCA2a deacetylation. Muscle-specific SIRT3 overexpression may not prevent the complications associated with an unhealthy diet in mice, but it appears to enhance SERCA2a activity in the mouse heart.

Cardioprotective Effects of Dietary Flaxseed Post-Infarction Are Associated with Changes in MicroRNA Expression.

MicroRNAs (miRNAs/miRs) such as miR-1, miR-133a, miR-133b, miR-135a, and miR-29b play a key role in many cardiac pathological remodeling processes, including apoptosis, fibrosis, and arrhythmias, after a myocardial infarction (MI). Dietary flaxseed has demonstrated a protective effect against an MI. The present study was carried out to test the hypothesis that dietary flaxseed supplementation before and after an MI regulates the expression of above-mentioned miRNAs to produce its cardioprotective effect. Animals were randomized after inducing MI by coronary artery ligation into: (a) sham MI with normal chow, (b) MI with normal chow, and (c-e) MI supplemented with either 10% milled flaxseed, or 4.4% flax oil enriched in alpha-linolenic acid (ALA), or 0.44% flax lignan secoisolariciresinol diglucoside. The feeding protocol consisted of 2 weeks before and 8 weeks after the surgery. Dietary flax oil supplementation selectively upregulated the cardiac expression of miR-133a, miR-135a, and miR-29b. The levels of collagen I expression were reduced in the flax oil group. We conclude that miR-133a, miR-135a, and miR-29b are sensitive to dietary flax oil, likely due to its rich ALA content. The cardioprotective effect of flaxseed in an MI could be due to modulation of these miRNAs.

Mechanisms of myocyte cytotoxicity induced by the multiple receptor tyrosine kinase inhibitor sunitinib.

The anticancer tyrosine kinase inhibitor sunitinib has been shown recently to be cardiotoxic. Using a neonatal rat myocyte model, we investigated various mechanisms that might be responsible for its cardiotoxicity. Sunitinib potently inhibited the enzyme activity of both AMP-activated protein kinase (AMPK) and the ribosomal S6 kinase RSK1 at therapeutically relevant concentrations. Heart tissue with its high energy needs might be particularly sensitive to inhibition of AMPK because of its role as an energy sensor regulating ATP levels. As measured by lactate dehydrogenase release, sunitinib treatment of myocytes caused dose-dependent damage at therapeutic levels. Sunitinib treatment also caused a dose-dependent reduction in myocyte protein levels of the phosphorylated alpha and beta isoforms of the AMPK phosphorylation target acetyl-Coenzyme A carboxylase. However, myocytes were not protected from sunitinib treatment by pretreating them with the AMPK-activating antidiabetic drug metformin. Sunitinib treatment of myocytes also did not affect cellular ATP levels. Together, these last two results do not suggest a major role for inhibition of AMPK in sunitinib-induced myocyte damage. Dexrazoxane, which is a clinically approved doxorubicin cardioprotective agent, also did not protect myocytes from damage, which suggests that sunitinib did not induce oxidative damage. In conclusion, even though sunitinib potently inhibits AMPK and RSK1, given the extreme lack of kinase selectivity that sunitinib exhibits, it is likely that inhibition of other kinases or combinations of kinases are responsible for the cardiotoxic effects of sunitinib.

Cr(VI)-stimulated STAT3 tyrosine phosphorylation and nuclear translocation in human airway epithelial cells requires Lck.

Chronic inhalation of low amounts of Cr(VI) promotes pulmonary diseases and cancers through poorly defined mechanisms. SFKs (Src family kinases) in pulmonary airway cells may mediate Cr(VI) signalling for lung injury, although the downstream effectors of Cr(VI)-stimulated SFKs and how they relate to pathogenic gene induction are unknown. Therefore SFK-dependent activation of transcription factors by non-cytotoxic exposure of human bronchial epithelial cells to Cr(VI) was determined. Protein-DNA binding arrays demonstrated that exposing BEAS 2B cells to 5 microM Cr(VI) for 4 and 24 h resulted in increased protein binding to 25 and 43 cis-elements respectively, while binding to 12 and 16 cis-elements decreased. Of note, Cr(VI) increased protein binding to several STAT (signal transducer and activator of transcription) cis-elements. Cr(VI) stimulated acute tyrosine phosphorylation and nuclear translocation of STAT1 over a 4 h period and a prolonged activation of STAT3 that reached a peak between 48 and 72 h. This prolonged activation was observed for both STAT3alpha and STAT3beta. Immunofluorescent confocal microscopy confirmed that Cr(VI) increased nuclear localization of phosphorylated STAT3 for more than 72 h in both primary and BEAS 2B human airway cells. Cr(VI) induced transactivation of both a STAT3-driven luciferase reporter construct and the endogenous inflammatory gene IL-6 (interleukin-6). Inhibition with siRNA (small interfering RNA) targeting the SFK Lck, but not dominant-negative JAK (Janus kinase), prevented Cr(VI)-stimulated phosphorylation of both STAT3 isoforms and induction of IL-6. The results suggest that Cr(VI) activates epithelial cell Lck to signal for prolonged STAT3 activation and transactivation of IL-6, an important immunomodulator of lung disease progression.

Mechanism of the cytotoxicity of the diazoparaquinone antitumor antibiotic kinamycin F.

The bacterial metabolite kinamycin F, which is being investigated as a potent antitumor agent, contains an unusual and potentially reactive diazo group, a paraquinone, and a phenol functional group. Kinamycin F reacted with glutathione (GSH) in a complex series of reactions which suggested that kinamycin F may have its cytotoxicity modulated by GSH. Consistent with this idea, 2-oxo-4-thiazolidinecarboxylic acid treatment to increase cellular GSH levels and buthionine sulfoximine treatment to decrease GSH levels resulted in decreased and increased kinamycin F cytotoxicity, respectively, in K562 leukemia cells. Kinamycin F weakly bound to DNA and induced DNA damage in K562 cells that was independent of GSH levels. The GSH-promoted DNA nicking induced by kinamycin F in vitro was attenuated by deferoxamine, dimethyl sulfoxide, and catalase, which indicated that DNA damage initiated by this agent occurred in an iron-, hydrogen-peroxide-, and hydroxyl-radical-dependent manner. Electron paramagnetic resonance spectroscopy experiments showed that the GSH/kinamycin F system produced a semiquinone free radical and that the hydrogen peroxide/peroxidase/kinamycin F system generated a phenoxyl free radical. In conclusion, the results indicated that kinamycin F cytotoxicity may be due to reductive and/or peroxidative activation to produce DNA-and protein-damaging species.

The interpersonal context of client motivational language in cognitive-behavioral therapy.

Previous research has found that client motivational language (especially arguments against change or counterchange talk; CCT) in early therapy sessions is a reliable predictor of therapy process and outcomes across a broad range of treatments including cognitive-behavioral therapy (CBT). Existing studies have considered the general occurrence of CCT, but the present study differentiated 2 types of CCT in early CBT sessions for 37 clients with generalized anxiety disorder: (a) statements that are uttered to express ambivalence regarding change versus (b) statements that are intended to oppose the therapist or therapy. Two process coding systems were used to accomplish this differentiation. Findings indicated that a higher number of CCT statements that occurred in the presence of resistance (opposition to the therapist or therapy) were a substantive and consistent predictor of lower homework compliance and poorer outcomes, up to 1 year posttreatment. Moreover, when both types of CCT were considered together, only opposition CCT was related to outcomes, and ambivalent CCT was not significantly predictive of proximal and distal outcomes. These findings suggest that the interpersonal context in which CCT statements occur may be critically important to their predictive capacity. More broadly, the findings of this study have implications for the future study of client motivational language and underscore the clinical importance of detecting opposition CCT.

Conjugated linoleic acid prevents high glucose-induced hypertrophy and contractile dysfunction in adult rat cardiomyocytes.

Diabetes mellitus is associated with increased risk and incidence of cardiovascular morbidity and mortality, independently of other risk factors typically associated with diabetes such as coronary artery disease and hypertension. This promotes the development of a distinct condition of the heart muscle known as diabetic cardiomyopathy. We have previously shown that conjugated linoleic acid (CLA) prevents endothelin-1-induced cardiomyocyte hypertrophy. However, the effects of CLA in preventing alterations in cardiomyocyte structure and function due to high glucose are unknown. We therefore hypothesized that CLA will have protective effects in an in vitro model of diabetic cardiomyopathy using adult rat cardiomyocytes exposed to high glucose. Our results demonstrate that subjecting adult rat cardiomyocytes to high glucose (25 mmol/L) for 24 hours significantly impaired the contractile function as evidenced by decreases in maximal velocity of shortening, peak shortening, and maximal velocity of relengthening. High glucose-induced contractile dysfunction was inhibited by pretreatment with CLA (30 µmol/L; 1 hour). In addition to contractile aberrations, exposing adult rat cardiomyocytes to high glucose for 48 hours induced cardiomyocyte hypertrophy. High glucose-induced cardiomyocyte hypertrophy was likewise prevented by CLA. The antihypertrophic effects of CLA were abolished when cardiomyocytes were pretreated with the pharmacologic inhibitor of peroxisome proliferator-activated receptor γ, GW9662 (1 µmol/L). In conclusion, our findings show that exposing cardiomyocytes to high glucose results in cardiomyocyte functional and structural abnormalities, and these abnormalities are prevented by pretreatment with CLA and mediated, in part, by peroxisome proliferator-activated receptor γ activation.

It's a matter of time: The effect of depletion on communal action in romantic relationships is moderated by relationship length.

Researchers have only begun to turn their attention to the role of self-control in communal action (rather than communal restraint) in relationships. Conflicting results from early studies indicate that the association between self-control and communal action may be quite complex, and potentially moderated by many variables. Here we investigate how relationship length may moderate the extent to which communal actions require self-control resources. In 5 studies, we investigated the role of self-control resources in implementing (Studies 1 and 2) and in choosing (Studies 3-5) communal actions for a romantic partner, as a function of the length of time partners had been together. The data supported the hypothesis that as relationships mature over time, communal actions may require less self-control to implement and may become a decisional default. These findings suggest that communal actions may be a more deliberative response in newer romantic relationships but a more reflexive response in more established relationships.

Metal-induced cell signaling and gene activation in lung diseases.

Chronic environmental and occupational exposures to low levels of metals are associated with increased incidence of pulmonary and cardiopulmonary diseases. The cellular and molecular mechanisms of action of metals in the lung are unresolved and involve complex pleiotrophic effects. These effects are mediated by direct reaction of the metals with cellular macromolecules and indirect effects of reactive oxygen species generated when cells are exposed to metals. This review focuses on cell signaling pathways activated by two metals, chromium and nickel, that are known to promote a variety of lung diseases, including fibrosis, obstructive disease, and cancer. These signaling pathways are discussed in relation to the inclusion or exclusion of reactive oxygen in mediating cellular activation following metal exposures.

Genomic and proteomic profiling of responses to toxic metals in human lung cells.

Examining global effects of toxic metals on gene expression can be useful for elucidating patterns of biological response, discovering underlying mechanisms of toxicity, and identifying candidate metal-specific genetic markers of exposure and response. Using a 1,200 gene nylon array, we examined changes in gene expression following low-dose, acute exposures of cadmium, chromium, arsenic, nickel, or mitomycin C (MMC) in BEAS-2B human bronchial epithelial cells. Total RNA was isolated from cells exposed to 3 M Cd(II) (as cadmium chloride), 10 M Cr(VI) (as sodium dichromate), 3 g/cm2 Ni(II) (as nickel subsulfide), 5 M or 50 M As(III) (as sodium arsenite), or 1 M MMC for 4 hr. Expression changes were verified at the protein level for several genes. Only a small subset of genes was differentially expressed in response to each agent: Cd, Cr, Ni, As (5 M), As (50 M), and MMC each differentially altered the expression of 25, 44, 31, 110, 65, and 16 individual genes, respectively. Few genes were commonly expressed among the various treatments. Only one gene was altered in response to all four metals (hsp90), and no gene overlapped among all five treatments. We also compared low-dose (5 M, noncytotoxic) and high-dose (50 M, cytotoxic) arsenic treatments, which surprisingly, affected expression of almost completely nonoverlapping subsets of genes, suggesting a threshold switch from a survival-based biological response at low doses to a death response at high doses.