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This paper aims to compare mental and physical health, cognitive functioning, and selected biomarkers of aging reflecting metabolic pathology and inflammation, in outpatients with schizophrenia from two residential settings: residential care facilities (RCFs) and living with someone in a house/apartment. This cross-sectional study examined community-dwelling adults with schizophrenia either in RCFs (N = 100) or in a house/apartment with someone (N = 76), recruited for two NIH-funded studies in San Diego. Assessments included measures of mental/physical health, cognitive function, and metabolic (glycosylated hemoglobin, cholesterol) and inflammatory (C-Reactive Protein, Tumor Necrosis Factor-alpha, Interleukin-6) biomarkers of aging. General logistic models were used to analyze factors associated with residential status. RCF residents had several indicators of worse prognosis (never being married, higher daily antipsychotic dosages, increased comorbidities and higher Framingham risk for coronary heart disease) than individuals living with someone. However, RCF residents had better mental well-being and lower BMI, as well as comparable biomarkers of aging as those living with someone. While the cross-sectional nature of the study does not allow us to infer causality, it is possible that the supportive environment of RCFs may have a positive impact on mental and physical health of persons with schizophrenia. Longitudinal follow-up studies are needed to test this hypothesis.

Background and objectives Posttraumatic stress disorder (PTSD) is a chronic, disabling, and prevalent mental health disorder among Veterans. Despite the availability of empirically supported psychotherapies, many Veterans remain symptomatic after treatment and/or prefer to seek complementary and integrative health approaches, including yoga, to manage PTSD. The randomized controlled trial (RCT) described herein will evaluate the efficacy of a manualized yoga program as compared to nonaerobic exercise in reducing PTSD severity among Veterans. A secondary aim of this study is to better understand the mechanisms of change. Methods Veterans (N = 192) with PTSD will be randomized to hatha yoga or nonaerobic physical activity control; both groups consist of 12 weekly, 60-min group or online training sessions with 15–20 min of daily at-home practice. Outcome measures will be administered at baseline, mid-treatment, posttreatment, and 12-week follow-up. Projected outcomes This study will evaluate changes in PTSD severity (primary outcome) as well as depression, anxiety, anger, sleep problems, and psychosocial disability (secondary outcomes). We will also use multiple mediation to examine two potential models of the mechanisms of clinical effect: the Attention Model (i.e., yoga increases attentional control, which reduces PTSD symptoms), the Coping Model (i.e., yoga increases distress tolerance, which improves coping, which reduces PTSD symptoms), and the combination of these models. This aspect of the study is innovative and important given the absence of an existing, comprehensive model for understanding yoga's impact on PTSD. Ultimately, we hope to develop guidelines for application of yoga to PTSD recovery., Highlights • Many Veterans with PTSD remain symptomatic after treatment or prefer alternatives. • Yoga is a promising PTSD treatment, but evidence is mixed and of limited quality. • This study is a large randomized controlled trial of yoga vs. nonaerobic exercise. • Treatment effects may be driven by change in attentional control and coping. • COVID-19 necessitated changes, creating an opportunity to examine remote delivery.

Background Previous literature suggests that better cognitive ability and insight are associated with greater lifetime risk of suicide attempts in schizophrenia, counter to the direction of association in the general population. However, the conjoint association between distinct cognitive domains, insight, and suicidality has not been assessed. Method In a cross-sectional study, 162 adults with schizophrenia or schizoaffective disorder completed cognitive testing via the MATRICS battery, symptom and cognitive insight assessments, along with the Columbia Suicide Severity Rating Scale. We then contrasted participants based on history of suicidality by cognitive domains and insight measures and conducted multivariate analyses. Results Although a history of any passive ideation was not associated with cognitive ability or insight, verbal learning was positively associated with a greater history of suicidal attempt and prior ideation with a plan and intent. Higher cognitive insight, and the self-reflectiveness subscale insight, was also associated with history of passive or active suicidal ideation. Cognitive insight and cognitive ability were independent from each other, and there were no moderating influences of insight on the effect of cognitive ability on suicide related history. Exploratory analyses revealed that history of planned attempts were associated with greater verbal learning, whereas histories of aborted attempts were associated with poorer reasoning and problem-solving. Implications Although cross-sectional and retrospective, this study provides support that greater cognitive ability, specifically verbal learning, along with self-reflectiveness, may confer elevated risk for more severe suicidal ideation and behavior in an independent fashion. Interestingly, poorer problem-solving was associated with aborted suicide attempts.

People have much to gain from regular exercise, such as improved sleep, increased cognitive function, and reduced risk for cardiovascular disease, and these benefits may be particularly important for people experiencing deficits in these areas due to depressive symptoms (Kubesch et al., 2003; Lett et al., 2004; Rethorst et al., 2013). Moreover, regular exercise can be an effective treatment for depression (Babyak et al., 2000; Dunn et al., 2005; Mather et al., 2002; Mota-Pereira et al., 2011; Rethorst, Wipfli, & Landers, 2009). Despite the myriad benefits of regular exercise, adults with depressive symptoms have lower exercise levels than other adults (Patten, Williams, Lavorato, & Eliasziw, 2009; Roshaneai-Moghaddam, Katon, & Russo, 2009) and those with depressive symptoms who initiate a regular exercise regimen are more likely than others to discontinue it (DiMatteo, Lepper, & Croghan, 2000; Teixeira et al., 2004). Therefore, it is important to understand the reasons why people with depressive symptoms have difficulty initiating and maintaining regular exercise. Models of health behavior change, such as the Health Action Process Approach, Theory of Planned Behavior, and Social Cognitive Theory, emphasize the role of self-efficacy in successful behavior change (Ajzen, 1991; Bandura, 1997; Schwarzer, 1992). Self-efficacy is a person’s belief in his or her own ability to execute a specific behavior (Bandura, 1997), and it is central to behavior change because it guides what behaviors people choose to engage in and how people respond to obstacles and challenges in changing their behaviors (Bandura, 1997). Self-efficacy is known to be a predictor of successful initiation and maintenance of regular exercise (Rodgers, Hall, Blanchard, McAuley, & Munroe, 2002; Williams et al., 2008). Low self-efficacy may be one reason why people with depressive symptoms have difficulties initiating and maintaining regular exercise. People with depressive symptoms report lower self-efficacy than people without depressive symptoms across various behaviors (Bandura, 1998; Robinson-Smith, Johnston & Allen, 2000; Sacco et al., 2005). However, to date, it is unclear how depressive symptoms affect people’s self-efficacy while they attempt to initiate regular exercise. Self-efficacy beliefs are based on perceptions of ability to execute the relevant behavior, as well as perceptions of specific task demands and situational circumstances. Self-efficacy is theorized to stem from four sources: personal experience, vicarious experience, social persuasion (e.g., verbal encouragement), and physiological factors (e.g., arousal such as increased heart rate can lead to perceived inefficacy). Among these different sources, personal experience in executing the relevant behavior is the strongest source of self-efficacy perceptions (Bandura, 1997). Consistent with the proposition that personal experience is the strongest source of self-efficacy, exercise self-efficacy has been shown to significantly increase following participation in exercise. This has been observed after individual bouts of exercise (McAuley, 1995; McAuley et al., 2011) and long-term interventions for regular exercise (Marcus, Selby, Niaura, & Rossi, 1992; McAuley, 1995). This pattern of self-efficacy increases following the execution of exercise is consistent across the literature among healthy adults (Keller, Fleury, Gregor-Holt, & Thompson, 1999). In contrast, self-efficacy has been shown to decrease when individuals do not adhere to regular exercise, especially during the initiation of regular exercise as a new behavior (Parschau, Richert, Koring, Lippke, & Schwarzer, 2012). These findings all demonstrate that perceptions of self-efficacy are sensitive to whether people are successfully engaging in exercise or not. However, Bandura (1997) emphasized that it is not simply objective task execution that influences self-efficacy, but also the subjective perceptions and interpretations associated with the behavior. Subjective perceptions can be influenced by personal factors, such as differences in affective and cognitive processing. Depressive symptoms may be a personal factor that moderates the path between personal experience with exercise and self-efficacy. Depression is characterized by negative interpretations of experiences that are influenced by rumination, negative cognitions, and negative recall bias (Beck, 1991). The result of these negative interpretations is a tendency to minimize successes and exaggerate failures (Bandura, 1997). There is evidence to suggest that depressive symptoms influence self-efficacy to exercise regularly, but the evidence does not specifically address how this occurs. For example, older adults with depressive symptoms who enrolled in a 10-week progressive resistance-training program did not report increases in self-efficacy despite regular participation in exercise and objective gains in physical capability (Singh et al., 1997). This finding suggests the possibility that people with depressive symptoms have difficulties deriving self-efficacy from successfully performing exercise. This would be consistent with evidence that depressive symptoms are associated with a tendency to minimize successes (Bandura, 1997; Beck, 1991). Alternatively, Conroy and colleagues (2007) analyzed cross-sectional data one year after an exercise intervention in order to understand lapses (i.e., two weeks of failed adherence) during the initiation of a regular exercise regimen. They found that participants with high depressive symptoms were more likely than other participants to never return to regular exercise after a lapse to inactivity. This suggests that not exercising for two weeks was more detrimental to regular exercise behavior for participants with high depressive symptoms than those with low symptoms. One possible explanation is that participants with depressive symptoms may have experienced greater decreases in self-efficacy when they did not exercise regularly. This would be consistent with evidence that depressive symptoms can also be associated with a tendency to exaggerate failures (Bandura, 1997; Beck, 1991). However, this possibility was not directly examined. If depressive symptoms moderate the relation between exercise and self-efficacy, the moderation effect could be manifest in two different ways. First, depressive symptoms may dampen an increase in self-efficacy when people exercise (e.g., self-efficacy is lower for people with high depressive symptoms than those with low symptoms on days they exercise). Second, depressive symptoms may amplify a decrease in self-efficacy when people do not exercise (e.g., self-efficacy is lower for people with high depressive symptoms than those with low symptoms on days they do not exercise). Current evidence is unclear as to whether either or both effects occur for people with depressive symptoms (Singh et al., 1997; Conroy et al., 2007). Elucidating how these effects unfold on a daily basis would help specify why people with depressive symptoms have difficulties initiating regular exercise. Self-efficacy and exercise both have unique features that would benefit from daily examination over time. First, self-efficacy is not a static construct; it varies according to a person’s experiences (Shiffman et al., 2000). Second, the first days and weeks of initiating regular exercise are a sensitive period in both the formation of self-efficacy (Bandura, 1997) and establishing regular exercise (Dishman, Ickes, & Morgan, 1980), thus it is likely that exercise self-efficacy will be particularly sensitive to daily influences during this critical phase. Third, regular exercise is a health behavior that does not necessitate daily adherence, unlike other health behaviors such as smoking cessation or medication adherence. Indeed, public health guidelines for physical activity recommend activity on most but not all days of the week (USDHHS, 2008). Consequently, for people initiating regular exercise, there will routinely be days on which they exercise and days on which they do not. Distinguishing between experiences that occur on days of exercise and days of no exercise is relevant to understanding the daily psychological processes that occur during the initiation phase of regular exercise.

Federal law has prohibited the purchase and possession of firearms on the basis of mental health for nearly 50 years. The current background check system is limited by its vague policies, nonmandatory reporting standards, and low cooperation of individual states with the national background check registry. In January 2013, the Obama administration began an effort to reduce gun violence, which included proposed reform to mental health reporting standards and to the national background check system. However, there is much debate over whether people with mental illness should be included in background check databases or if their inclusion is counterproductive to the treatment of mental illness and the prevention of gun violence. The literature suggests that mental illness is not a reliable predictor of violence, rather a history of violence and current threats of violence are the best predictors of future violence. This article discusses the ethical considerations of mental health background checks for firearm ownership, with particular regard to the differing confidentiality policies of mental health professionals across states and the potential ramifications of a national mental health registry on patients' well-being. We propose that gun control regulations should implement empirically supported predictors of violence and that national inconsistencies in policies regarding confidentiality and "duty to warn" should be resolved. Language: en

The aims were to predict cognitive therapy (CT) noncompletion and to determine, relative to other putative predictors, the extent to which the patient skills in CT for recurrent major depressive disorder predicted response in a large, two-site trial.Among 523 outpatients aged 18e70, exposed to 12e14 weeks of CT, 21.6% dropped out. Of the 410 completers, 26.1% did not respond. To predict these outcomes, we conducted logistic regression analyses of demographics, pre-treatment illness characteristics and psychosocial measures, and midtreatment therapeutic alliance.The 17-item Hamilton Rating Scale for Depression (HRSD17) scores at entry predicted dropout and nonresponse. Patients working for pay, of non-Hispanic white race, who were older, or had more education were significantly more likely to complete. Controlling for HRSD17, significant predictors of nonresponse included: lower scores on the Skills of Cognitive Therapy-Observer Version (SoCT-O), not working for pay, history of only two depressive episodes, greater pre-treatment social impairment. Midphase symptom reduction was a strong predictor of final outcome.These prognostic indicators forecast which patients tend to be optimal candidates for standard CT, as well as which patients may benefit from changes in therapy, its focus, or from alternate modalities of treatment. Pending replication, the findings underscore the importance of promoting patients’ understanding and use of CT skills, as well as reducing depressive symptoms early. Future research may determine the extent to which these findings generalize to other therapies, providers who vary in competency, and patients with other depressive subtypes or disorders.

Item does not contain fulltext Physical activity (PA) interventions have a clear role in promoting mental health. Current PA guidelines directed toward specific PA intensities may have negative effects on affective response to exercise, and affective response is an important determinant of PA adherence. In this randomized trial of 67 previously inactive adults, we compared the effects of a PA prescription emphasizing the maintenance of positive affect to one emphasizing a target heart rate, and tested the extent to which the effect of the affect-guided prescription on PA is moderated by cardiorespiratory fitness (CRF). We found the effect of an affect-guided prescription was significantly moderated by CRF. At one week, for participants with lower CRF (i.e. poor conditioning), the affect-guided prescription resulted in significantly greater change in PA minutes (M = 240.8) than the heart rate-guided prescription (M = 165.7), reflecting a moderate-sized effect (d = .55). For those with higher CRF (i.e. good conditioning), the means were in the opposite direction but not significantly different. At one month, the same pattern emerged but the interaction was not significant. We discuss the implications of these findings for the type of PA prescriptions offered to individuals in need. 13 p.

The effect of a single halothane anaesthesia on the secondary antibody response and the lymphocyte response in vitro to phytohaemagglutinin (PHA) and concanavalin A (Con A) was studied. The antigens used were bovine serum albumin (BSA) and killed Brucella abortus organisms (Brucella). IgG and IgM antibodies against these antigens were quantified by solid-phase radioimmunoassay. Lymphocyte transformation was studied by a whole blood micromethod. The chickens were anaesthetised for two hours with 2% v/v halothane. The halothane concentration of the blood was measured by gas chromatography at the end of the anaesthesia. Halothane anaesthesia had no effect on the secondary antibody response against BSA and Brucella. In contrast, it caused a significant decrease in the lymphocyte response to PHA and Con A. This suppression was transient, however, and full recovery of the lymphocyte function was observed by the first day after anaesthesia.

The pharmacokinetics of nitrazepam in saliva and serum was studied in 12 healthy volunteers after a single administration of a 5 mg nitrazepam tablet. The binding of nitrazepam to plasma proteins was determined 4 hours after the administration by ultracentrifugation. The analysis of nitrazepam concentrations was performed by 63Ni-EC-GLC. The pharmacokinetic parameters were evaluated manually or by AUTOAN-program in serum, and manually in saliva. The concentrations of nitrazepam in serum and saliva correlated significantly (r = 0.472, P less than 0.001, n = 97). The ratio saliva: serum was, however, time dependent. The protein free fraction in serum was significantly higher (P less than 0.01) than the salivary concentration at the same time (4 hours after administration). The peak concentrations in serum and saliva were 40.7 and 1.9 ng/ml (P less than 0.001) and the times to reach the peak maximum 2.4 and 2.5 hours, respectively (difference not significant). The mean half-life of nitrazepam in serum was 30.5 hrs and in saliva 39.9 hrs, the difference being significant at P less than 0.05. The distribution phase parameters, poorly described before, were calculated. The clinical value of nitrazepam analysis in saliva seems to be negligible.

Diazepam (tensopam®) 10 mg was given orally to 12 chronic alcoholic patients, at the beginning of the alcohol-free period and to 14 controls. Diazepam in the plasma was determined gaschromatographically with a 63Ni-EC detector. During the absorption phase the plasma levels of diazepam were reduced to 44% at 2 hours (P < 0.01) and 32% at 3.5 hours (P < 0.001) in alcoholic patients compared with respective values of normal subjects. The reduced values, found in the alcoholic patients, may be due to disturbances in the gastro-intestinal absorption of diazepam, or to processes involving the portal vein or liver. Some alcoholic patients received a simultaneous treatment with neuroleptic or hypnotic drugs.

Concentrations of nitrazepam in plasma were determined by gas chromatography in healthy volunteers after an acute peroral administration of nitrazepam (5 and 10 mg). Placebo tablets were also used, and an assessement of subjective drug effects was made during each medication. In addition serum growth hormone levels were determined. The peak plasma nitrazepam concentration was achieved at 120 minutes (46.9 +/- 3.2 ng/ml, mean +/- S.E.M.) after 5 mg of nitrazepam and at 180 minutes (82.8 +/- 10.5 ng/ml) after the dose of 10 mg. The half-life of nitrazepam in plasma ranged from 16.5 to 48.3 (mean 28.8) hours. A significant positive correlation was seen between the subjective sedative effects and the magnitude of the peak nitrazepam concentrations in plasma. This drug effect was highly significant when the plasma levels of nitrazepam were rising. The subjective sedative effects were more prominent after 10 mg than after 5 mg dose of nitrazepam. The plasma nitrazepam concentration was not significantly correlated with the subjective sedative effect the next morning, 12 hours after the drug intake. Serum growth hormone levels rose significantly during the study both after 5 mg and 10 mg nitrazepam doses (peak levels 16.3 +/- 4.0 and 12.7 +/- 3.1 ng/ml) and were significantly higher than after placebo administration (3.7 +/- 0.7 ng/ml).

Taking account of both intrinsic and environmental determinants, Kogan (2002a, b) describes possible interactions between them in a developmental model of performing-arts careers. An alternative model of talent development is offered by Simonton (1999, 2001), who has drawn upon the earlier behavior-genetic research of Lykken (1982), particularly the concept of emergenesis. Questionnaire data from a sample of 122 students in the Actors Studio drama school was examined for its consistency with the Lykken-Simonton emergenesis model. Consistent with the model's expectations, parental professional participation in the dramatic arts was very low, age at which students decided to pursue a dramatic-arts career varied widely, and students' prior school and undergraduate college experience exhibited considerable heterogeneity. The relative merits of a model based entirely on genetic trajectories are discussed in comparison with interactive and purely environmental models. Given the limited empirical base, however, it is far from evident which approach offers the greatest potential for predicting who will become the best actors, directors, and playwrights of the future.

Ospemifene is a tissue-selective estrogen agonist/antagonist that was recently approved for the treatment of dyspareunia associated with vulvar and vaginal atrophy, which occurs in up to approximately 50% of postmenopausal women. The current analyses were conducted to determine whether ospemifene exhibits estrogenic activity in the mammary glands of ovariectomized rats and to compare potential estrogenic activity with selective estrogen receptor modulators (tamoxifen, raloxifene, and toremifene). Three separate studies with differing durations (6, 9, and 28 days) were conducted using similar procedures in ovariectomized Sprague-Dawley rats. Estradiol treatment and sham-treated ovariectomized rats were used as positive and negative controls, respectively. Cell proliferation was examined using labeled 5-bromo-2-deoxyuridine; cytoplasmic prolactin was characterized with antibody staining. The morphology of the mammary gland was studied by histological staining of sections from the right fourth mammary glands, and the excised gland from the left side was used for counting the lobulus number. Neither ospemifene nor selective estrogen receptor modulators substantially induced 5-bromo-2-deoxyuridine staining, altered the morphology of the mammary glands, or changed prolactin immunostaining in ovariectomized rats compared with the ovariectomized controls. With the exception of toremifene, the selective estrogen receptor modulators did not cause a substantial induction in mammary gland lobuli. Estradiol had effects opposite to those of the selective estrogen receptor modulators in these studies. Ospemifene exhibited no substantial estrogenic activity in the mammary gland of ovariectomized rats. Activity in the mammary gland of ovariectomized rats with ospemifene was comparable to raloxifene and tamoxifen.

Dura-Guard Dural Repair Patch, PRECLUDE Dura Substitute, and Codman ETHISORB Dura Patch were evaluated in a six-month dural tissue reaction study in rabbits. Bilateral craniotomy was followed by subdural implantation for each dura mater substitute. The surgical procedure for the sham control group was the same except that no material was implanted. Implantation of all of these dura mater substitutes for 28, 91, or 182 days post-implantation did not result in any deaths or clinical neurobehavioral abnormalities, changes in cerebrospinal fluid, or significant macroscopic changes at necropsy. However, histomorphologic evaluation of the implantation sites revealed some differences in the tissue response to these materials. For Dura-Guard Dural Repair Patch, a nonabsorbable material derived from bovine pericardium, the implantation site was characterized by fibrosis of the overlying area with islands of osseous metaplasia and adhesions to the brain surface. Over time, infiltrative fibrosis of the implant resulted in separation of the collagenous layers of the implant and compression of the underlying brain. Fibrosis of the overlying area that incorporated this material formed a 'replacement' dura mater. Adhesions to the brain surface observed initially were still present at six months post-implantation. Implantation of PRECLUDE Dura Substitute, a nonabsorbable material comprised of expanded polytetrafluoroethylene, resulted in virtually no early reaction, and few adhesions to the brain surface at any time period. Although this material was eventually incorporated by fibrosis, islands of osseous metaplasia were also observed in this 'replacement' dura mater. The tissue reaction to Codman ETHISORB Dura Patch, an absorbable material comprised of polyglactin 910 and polydioxanone, was generally characterized by low-grade granulomatous inflammation and initial adhesions to the brain surface. The three-dimensional structure of this implant acted as a scaffold to guide the development and integration of a 'replacement' dura mater. The absorption of the material was associated with complete resolution of the inflammatory reaction, a lack of cerebral adhesions, and restoration of the normal architecture of this region. In conclusion, subdural implantation of Dura-Guard Dural Repair Patch, PRECLUDE Dura Substitute, or Codman ETHISORB Dura Patch in rabbits for up to six months resulted in the eventual restoration of the dura mater without significant adverse effects. However, osseous metaplasia associated with nonabsorbable Dura-Guard Dural Repair Patch and PRECLUDE Dura Substitute, and the infiltration of Dura-Guard Dural Repair Patch by fibrosis suggests that long-term follow-up may be needed after the use of these materials in patients. An advantage of Codman ETHISORB Dura Patch was that it was completely absorbed after guiding the restoration of the dura mater without any morphological sequelae.

The potential for the extraction of the plant lignan hydroxymatairesinol (HMR) in large scale from Norway spruce (Picea abies) has given us the opportunity to study the metabolism and biological actions of HMR in animals. HMR, the most abundant single component of spruce lignans, was metabolized to enterolactone (ENL) as the major metabolite in rats after oral administration. The amounts of urinary ENL increased with the dose of HMR (from 3 to 50 mg/kg), and only minor amounts of unmetabolized HMR isomers and other lignans were found in urine. HMR (15 mg/kg body wt po) given for 51 days decreased the number of growing tumors and increased the proportion of regressing and stabilized tumors in the rat dimethylbenz[a]anthracene-induced mammary tumor model. HMR (50 mg/kg body wt) did not exert estrogenic or antiestrogenic activity in the uterine growth test in immature rats. HMR also showed no antiandrogenic responses in the growth of accessory sex glands in adult male rats. Neither ENL nor enterodiol showed estrogenic or antiestrogenic activity via a classical alpha- or beta-type estrogen receptor-mediated pathway in vitro at1.0 microM. HMR was an effective antioxidant in vitro.

FC1271a is a novel triphenylethylene compound with a tissue-selective profile of estrogen agonistic and weak antagonistic effects. It specifically binds to the estrogen receptor alpha and beta with affinity closely similar to that of toremifene and tamoxifen. To study the in vivo effects of the compound, 4-month-old rats were sham operated (sham) or ovariectomized (OVX) and treated daily for 4 weeks with various doses of FC1271a or vehicle (orally). FC1271a was able to oppose OVX-induced bone loss by maintaining the trabecular bone volume of the distal femur. Accordingly, the OVX-induced loss of bone strength was prevented at doses of 1 and 10 mg/kg. FC1271a also prevented the OVX-induced increase in serum cholesterol in a dose-dependent manner. No significant changes in uterine wet weight or morphology were observed in the OVX-rats treated with 0.1 or 1 mg/kg FC1271a, but at a dose of 10 mg/kg it had a slightly estrogenic effect. In immature rats the effect of FC1271a on uterine wet weight was less stimulatory than that of toremifene or tamoxifen, but more stimulatory than that of raloxifene or droloxifene. The appearance of the dimethylbenzanthracene (DMBA)-induced mammary tumors was inhibited by treatment of DMBA-treated rats with FC1271a in a dose-dependent manner. In human MCF-7 breast cancer cell tumors raised in nude mice in the presence of estrogen, the growth and expression of pS2 marker gene could not be maintained after estrogen withdrawal by treatment with FC1271a. No formation of DNA adducts was observed in the liver of the FC1271a-treated rats. In conclusion, the bone-sparing, antitumor, and cholesterol-lowering effects of FC1271a combined with a low uterotropic activity and lack of liver toxicity indicate that FC1271a could be an important alternative in planning antiosteoporosis therapy for estrogen deficiency.

Ospemifene is a non-estrogen agent that exerts tissue-specific estrogen agonistic and weak antagonistic effects (i. e., is a selective estrogen receptor modulator [SERM]). The effects of various once-daily oral doses of ospemifene on bone are examined across 3 studies for 4 or 52 weeks after surgery in the ovariectomized (OVX) rat model of postmenopausal bone loss. Ospemifene treatment reduced the loss of bone mineral content and density observed in untreated OVX rats, significantly increased distal femur bone mineral content at 51 weeks at 25 mg/kg dose compared with untreated OVX rats (p

Satisfaction with physical activity is known to be an important factor in physical activity maintenance, but the factors that influence satisfaction are not well understood. The purpose of this study was to elucidate how ongoing experiences with recently initiated physical activity are associated with satisfaction. Participants (n = 116) included insufficiently active volunteers who initiated a self-directed physical activity regimen and completed daily diaries about their experiences for 28 days. We used multilevel models to examine the associations between experiences with physical activity and satisfaction. Significant between-person effects demonstrated that people reporting higher average levels of positive experiences and lower levels of thinking about the negative aspects of exercise were more likely to report higher levels of satisfaction (ps

PURPOSE Long-term effects of tamoxifen and toremifene, a new antiestrogen that closely resembles tamoxifen, were investigated on serum lipids and cholesterol metabolism. PATIENTS AND METHODS The study group consisted of 24 postmenopausal Finnish women with advanced breast cancer from an international multicenter study of 415 patients. Cholesterol metabolism was evaluated by measuring the cholesterol precursor (delta 8-cholestenol, desmosterol, and lathosterol, reflecting cholesterol synthesis) and plant sterol (markers of cholesterol absorption) and cholestanol levels by gas-liquid chromatography. RESULTS Tamoxifen and toremifene lowered significantly serum low-density lipoprotein (LDL) cholesterol levels after 12 months of treatment by 16% and 15%, with no change in high-density lipoprotein (HDL) cholesterol or serum triglyceride levels. Serum delta 8-cholestenol was increased 40- and 55-fold during toremifene and tamoxifen treatment, respectively, while the increase of desmosterol less than doubled and was lacking for lathosterol by toremifene. Plant sterols and cholestanol were only inconsistently increased in serum. CONCLUSION Tamoxifen and toremifene inhibit the conversion of delta 8-cholestenol to lathosterol so that serum total and LDL cholesterol levels are lowered by downregulation of cholesterol synthesis. Thus, inhibition of the delta 8-isomerase may be the major hypolipidemic effect of these agents. Reduced risk of coronary artery disease will probably occur also during long-term toremifene treatment, because the drug reduces cholesterol and its synthesis, similarly to tamoxifen.

The enzymatic hydrolysis and biological activity of a series of retinoates, esters of all-trans retinoic acid, were studied. Hydrolysis was conducted in pig liver esterase in aqueous solution. Toxicity was measured by brine shrimp (Artemia salina) bioassay and the anticancer effect by cell culture assay with human cancer ovarii cells and potato disc assay. Retinoates were effective in both tests, but their activities were lower than those of retinoic acid. The effects were related to the rate of hydrolysis. The reaction rates and the biological activities correlated with the molecular size and the retention factor measured by reversed-phase liquid chromatography.

An artificial neural network is developed for predicting which fragment is charged and which fragment is neutral for lipid fragment pairs produced from a liquid chromatography tandem mass spectrometry simulation process. This charge predictor is integrated into software developed at PNNL for in silico spectra generation and identification of metabolites known as Met ISIS. To test the effect of including charge prediction in Met ISIS, 46 lipids are used which show a reduction in false positive identifications when the charge predictor is utilized.

The glucose analogue 2-fluoro-2-deoxy-D-glucose (FDG) was used to study chemosensitivity of two human ovarian cancer cell lines and of murine L1210 cells. Cell viability was determined by measuring intracellular adenosine triphosphate (ATP) with a bioluminescence method, which has been shown to correlate closely with trypan blue, stem cell, and [3H]TdR assays. All three cell lines were sensitive to cytostatic drugs, which exerted a parallel decrease in the intracellular FDG and ATP levels. The two measures correlated positively (r = 0.66, P less than 0.001), indicating that FDG uptake is closely linked with ATP production. Relatively low hexokinase (HK)-to-glucose 6-phosphatase (HK/G6-Pase) ratios were measured, which suggests that the metabolic trapping of FDG 6-phosphate within the cytosol is incomplete. Apparently, these cell lines may not depend exclusively on glycolysis for their energy requirement. We conclude that cell killing caused by cytostatic drugs is associated with a decreased ATP content and FDG uptake. This indicates that not only ATP but also FDG may be used to study drug effects in vitro.

To investigate the pharmacokinetics of finrozole (MPV-2213ad), a novel competitive aromatase enzyme inhibitor, in healthy male volunteers.The study was an open, partly randomized cross-over study including 23 volunteers receiving single doses of 3, 9 mg or 30 mg of finrozole as tablets or solution with 14 days between the administrations. The highest dose was given as tablets only. Serum concentrations of finrozole were determined using high performance liquid chromatography combined with mass spectrometry.The mean time to peak serum concentration ranged from 2.5 to 3.1, and 0.6-0.7 h after tablets and solution, respectively. The Cmax values increased as the dose increased. The calculated apparent mean elimination half-life (t(1/2,z)) was approximately 3 h after the solution, and approximately 8 h after the tablet. The AUC(0,infinity) after finrozole tablets increased proportionally from 3 mg to 9 mg and from 3 to 30 mg. The calculated relative mean bioavailabilities (AUC(0,infinity)-ratio) for the 3 mg and 9 mg doses of finrozole as tablets were 89% and 78%, respectively.The absorption of finrozole from the tablet formulation was relatively rapid, and the apparent elimination half-life was longer after the tablet than after the solution, probably reflecting overlap of the absorption with the elimination phase.

FC1271a is a novel triphenylethylene compound with a tissue-selective profile of estrogen agonistic and weak antagonistic effects. It specifically binds to the estrogen receptor alpha and beta with affinity closely similar to that of toremifene and tamoxifen. To study the in vivo effects of the compound, 4-month-old rats were sham operated (sham) or ovariectomized (OVX) and treated daily for 4 weeks with various doses of FC1271a or vehicle (orally). FC1271a was able to oppose OVX-induced bone loss by maintaining the trabecular bone volume of the distal femur. Accordingly, the OVX-induced loss of bone strength was prevented at doses of 1 and 10 mg/kg. FC1271a also prevented the OVX-induced increase in serum cholesterol in a dose-dependent manner. No significant changes in uterine wet weight or morphology were observed in the OVX-rats treated with 0.1 or 1 mg/kg FC1271a, but at a dose of 10 mg/kg it had a slightly estrogenic effect. In immature rats the effect of FC1271a on uterine wet weight was less stimulatory than that of toremifene or tamoxifen, but more stimulatory than that of raloxifene or droloxifene. The appearance of the dimethylbenzanthracene (DMBA)-induced mammary tumors was inhibited by treatment of DMBA-treated rats with FC1271a in a dose-dependent manner. In human MCF-7 breast cancer cell tumors raised in nude mice in the presence of estrogen, the growth and expression of pS2 marker gene could not be maintained after estrogen withdrawal by treatment with FC1271a. No formation of DNA adducts was observed in the liver of the FC1271a-treated rats. In conclusion, the bone-sparing, antitumor, and cholesterol-lowering effects of FC1271a combined with a low uterotropic activity and lack of liver toxicity indicate that FC1271a could be an important alternative in planning antiosteoporosis therapy for estrogen deficiency.

The production of nidogen by four renal cell carcinoma (RCC) and three pancreatic adenocarcinoma (PAc) cell lines has been studied in cell culture and in xenografted tumours in nude mice. In RCC cells, immunoreactivity for nidogen was seen only after exposure to monensin to induce cytoplasmic accumulation of secretory proteins. In PAc cells, immunoreaction was also detectable in control cells. Immunoblotting of control and monensin-exposed cells and immunoprecipitation of culture media of radioactively labelled cells demonstrated the production of nidogen polypeptide of Mr ca. 150000 by six of the seven cell lines. Basement membranes (BMs) and stroma of the xenografted tumours derived from these six cell lines demonstrated immunoreactivity for both human and mouse nidogen, as revealed with species-specific antibodies. The ability of the cells to produce nidogen in vitro and deposit in vivo was positively correlated with high histological grade of the xenografted tumours, although the small number of cell lines studied calls for further studies to confirm this. The distribution of nidogen in human RCC and PAc specimens was also studied by immunohistochemistry. There was strong immunoreactivity for nidogen in tumour stroma, BM of carcinoma cell nests, and endothelial basal lamina, but no conclusions could be drawn regarding histological grade and immunostaining patterns, because stromal production could not be ruled out. The results show that nidogen is produced by human carcinoma cells both in vitro and in vivo.

Lymphokine activated killer (LAK) cells, cytotoxic T lymphocytes (CTL) and interleukin-2 (IL-2) all are being tested in cancer immunotherapy with modest success. The anti-estrogenic drug, toremifene (T0), was found earlier to amplify cancer immunotherapy with killer cells in mice. Here T0 is examined in combination with CTL and IL-2 in immunotherapy experiments.The P815 mastocytoma of DBA/2 mice was treated with combinations of CTL, LAK cells and T0 and combinations of CTL, IL-2 and T0 along with control groups. Tumor growth rate and mortality has been recorded.Combined treatment with CTL and LAK cells cured 25% of tumor bearing animals, as did treatment with tamoxifen (TX) or T0 alone. When killer cells were given in conjunction with anti-estrogens the cure rate was 75% with both TX and T0. Human recombinant IL-2 significantly inhibited tumor growth but no cures occurred. CTL alone cured 25% of the animals. When CTL and IL-2 treatment was given jointly with T0 75% of tumor bearing animals were cured.The results indicate that treatment with anti-estrogens increased the efficiency of immunotherapy by killer cells. This was true also when CTL therapy was supplemented with IL-2 treatment.

The triphenylethylene antiestrogenic agents, tamoxifen (TX) and toremifene (TO), are currently being used for the therapy of estrogen dependent breast carcinomas and for some other estrogen receptor positive tumors. Some observations indicate that these drugs may have a beneficial effect on estrogen receptor negative tumors as well.The H2712 mammary carcinoma of C3H/HeJ mice was studied in combination immunotherapy experiments using cytotoxic T lymphocytes (CTL) and TX or TO. The effect of TX and TO on the in vitro lysis of H2712 cells by CTL was also investigated. Finally, the H2712 cells were examined for the presence of estrogen receptors.Both TX and TO potentiated the lysis of H2712 cells by CTL in vitro, and exerted a growth inhibitory and therapeutic effect on H2712 mammary carcinomas in vivo. The therapeutic effect of CTL isolated from tumor bearing mice was improved on H2712 carcinomas when the animals were also treated orally by TX or TO. Using the dextran-coated charcoal assay, H2712 cells were found to be negative for classical estrogen receptors.These results indicate that the anti-estrogens, TX and TO, have the ability to suppress the growth of the estrogen receptor negative mammary carcinoma and to amplify target cell lysis by tumor-reactive CTL. By this mechanism these drugs enhance host immunity to an estrogen receptor negative tumor.

Efficacy and safety of toremifene 60 and 240 mg daily (TOR60 and TOR240) are compared to 40 mg tamoxifen daily (TAM40) in postmenopausal women with advanced estrogen receptor (ER) positive or ER unknown breast cancer. The study is randomized and open label in three parallel groups. Primary efficacy variables are response rate and time to progression. WHO and ECOG criteria were used for measurable and nonmeasurable disease assessment, respectively. Safety was reported according to WHO criteria. Altogether 463 patients were randomized (157 to TOR60, 157 to TOR240, and 149 to TAM40). By data cut-off, after 20.5 months median follow-up time, over 70% of the patients had experienced disease progression. Response rates are 20.4%, 28.7%, and 20.8% in TOR60. TOR240, and TAM40, respectively. TOR60 and TAM40 show statistically equivalent efficacy and the difference between TOR240 and TAM40 is not significant (P = 0.112). Median times to progression are 4.9 (TOR60), 6.1 (TOR240), and 5.0 (TAM40) months and the corresponding hazard ratios (TAM:TOR) 1.015 and 1.124. Again, TOR60 and TAM40 are statistically equivalent and the difference between TOR240 and TAM40 is not significant (P = 0.374). All treatments were well tolerated. As a conclusion, TOR60 and TAM40 show equivalent clinical efficacy and tolerability. The higher dose of toremifene slightly but not statistically significantly improves response rate and time to progression. In postmenopausal women, toremifene 60 mg daily is an effective and safe treatment of advanced ER-positive or ER-unknown breast cancer.

Overexpression of human ornithine decarboxylase (ODC) under the control of strong promoters induces morphological transformation of immortalized NIH3T3 and Rat-1 fibroblasts [M. Auvinen et al., Nature (Lond.), 360: 355-358, 1992]. We demonstrate here that ODC-overproducing NIH3T3 cells are tumorigenic in nude mice, giving rise to rapidly growing, large fibrosarcomas at the site of inoculation. The tumors are capable of invading host fat and muscle tissues and are vascularized abundantly. To disclose the molecular mechanism(s) driving the tumorigenic, invasive, and angiogenic phenotype of the tumors, the ODC-overproducing cell lines and tumor tissues were analyzed for the expression of various potential regulators and mediators of cell proliferation, matrix degradation, and angiogenesis. The tumorigenicity of ODC transformants was associated with elevated polyamine levels and down-regulated growth factor receptors. The invasiveness of the ODC-induced tumors could not be attributed to overexpression of various known extracellular matrix-degrading proteases or matrix metalloproteinases. The induction of the tumor neovascularization proved not to be elicited by vascular endothelial growth factor or basic fibroblast growth factor. Instead, the ODC-overexpressing cells appeared to secrete a novel angiogenic factor(s) that was able to promote migration of bovine capillary endothelial cells in collagen gels and increase the proliferation of human endothelial cells in vitro. In parallel, ODC-transformed cells displayed down-regulation of thrombospondin-1 and -2, the negative regulators of angiogenesis. Thus, the induction of the angiogenic phenotype of the ODC transformants is likely due both to increased expression and secretion of the new angiogenesis-stimulating factor(s) and decreased production and release of the antiangiogenic thrombospondins.

Type IV collagen trimer is a major component of basement membranes (BMs). It is composed of polypeptides named alpha1(IV)-alpha6(IV) chains. Chains alpha1,2(IV) are widely expressed in BMs while alpha3(IV)-alpha6(IV) are more restricted in human tissues. We have now studied by immunohistochemical means the distribution of collagen IV chains in fetal and adult human kidney, in oncocytomas, in renal cell carcinomas (RCCs) and their metastases and in experimental xenografts of human tumors. alpha1,2(IV) chains were found in all BMs of fetal and adult kidney as well as of renal tumors, while alpha3(IV)-alpha6(IV) chains were found in BMs of distal segments of developing and mature tubules. alpha3(IV)-alpha5(IV) chains were seen also in BMs of developing fetal glomeruli after the capillary loop stage. Most of the RCCs and their metastases showed occasional expression of alpha3(IV)-alpha6(IV) with papillary variants showing only expression of alpha5(IV) chain. There was a distinct expression of alpha3(IV)-alpha5(IV) chains in BMs of 3 oncocytomas. In 2 of them a variable expression of the alpha6(IV) chain was seen. In 3 of 4 xenografts, immunoreactivity for human-specific monoclonal antibody (MAb) for alpha1,2(IV) was seen in the BM-like structures. No alpha3-alpha6(IV) was seen in any of the xenografts, while polyclonal antiserum for type IV collagen presented immunoreactivity in BMs of all xenografts. Our results show that oncocytomas and most of the RCCs express scarce variants of type IV collagen containing alpha3(IV)-alpha6(IV) chains. In experimental xenograft tumors, both implanted RCC cells and host stromal cells have a capacity to produce type IV collagen.

Many animal and human tumors are infiltrated with killer cells. Recent studies have shown that the stimulation of such killer cells with interleukin-2 improves their tumor rejecting capacity. In this paper we demonstrate that the anti-estrogens, tamoxifen (TX) and toremifene (TO), enhance host resistance by sensitizing the tumor target to killer cell mediated lysis. The P815 mastocytoma syngeneic to DBA/21 mice was used. Cytotoxic T lymphocytes (CTL) were detected in the spleens of mice 12-14 days after tumor inoculation. In vitro target, effector, or both cell types were treated with either TX (1 microM) or TO (5 microM) for 4 hours prior to cytotoxicity testing by 51Cr release. Mice bearing P815 mastocytomas, 5 mm in diameter, were treated orally with TX or TO and were given CTL isolated from the spleens of tumor bearing donors i.p. Tumor growth, mortality, and immunological memory in cured animals were monitored. Both TX and TO treatment sensitized P815 target cells to lysis by CTL isolated from tumor bearing animals. The transfer of killer cells from the spleens of tumor bearing mice produced tumor suppression in the recipients, which could be enhanced by additional oral treatment by TX or TO. Complete cure was achieved in a significant number of animals, showing partial or complete resistance to a subsequent lethal dose of P815 cells. These experiments indicate that killer cells isolated from mice bearing progressive tumors can have an immunotherapeutic effect in syngeneic tumor bearing recipients and that the antiestrogens, TX and TO, may be used to potentiate the immunotherapy of this tumor.

It is well established that tamoxifen (TX) has a therapeutic effect on estrogen receptor positive tumors by inhibiting the binding of estradiol to its receptor. However, repeated clinical observations indicate that tamoxifen may also have beneficial effects on estrogen receptor negative tumors. In vitro cytotoxicity experiments were performed with the SL2-5 murine lymphoma using interleukin (IL)-2 activated syngeneic NK cells as effectors with or without TX or TO treatment. The effect of TX or TO (10 mg/kg/day/animal in feed) on the immunotherapy of SL2-5 lymphoma with syngeneic IL-2 activated NK cells was also investigated in syngeneic DBA/2 mice. Assays of SL2-5 cells for estrogen and progesterone receptors were also performed. Both TX and TO enhanced significantly the susceptibility of the SL2-5 lymphoma to lysis by IL-2 activated NK cells in vitro. When TX or TO treatment was combined with NK cell immunotherapy of this tumor, both drugs potentiated significantly tumor regression and cure rate when compared to groups receiving NK therapy alone. This tumor does not express classical receptors for estrogens or progesterone. These results indicate that combination treatment with the antiestrogens, TX and TO, acts synergistically with the immunotherapeutic effect of IL-2 activated NK cells in a syngeneic tumor host system.

Efficacy and safety of toremifene 60 and 240 mg daily (TOR 60 and TOR 240) are compared to 40 mg tamoxifen daily (NFV 40) in postmenopausal women with advanced estrogen receptor (ER) positive of ER unknown breast cancer. The study is randomized in three parallel groups. Primary efficacy variables are response rate and time to progression. WHO and ECOG criteria were used for measurable and nonmeasurable disease assessment, respectively. Safely was reported according to WHO criretia. Altogether 463 patients were randomized (157 to TOR 60, 157 to TOR 240 and 149 to TAM 40). By data cut-off, after 20.5 months medianfollow-up time, over 70% of the patients had experienced disease progression. Response rates are 20.4%, 28.7% in TOR 60, TOR 240 and TAM 40, respectively. TOR 60 and TAM 40 show statistically equivalent efficacy and the difference between TOR 240 and TAM 40 is not significant (P = 0.112). Median times to progression are 4.9 (TOR 60), 6.1 (TOR 240) and 5.0 (TAM 40) months and corresponding hazard ratios (TAM:TOR) 1.015 and 1.124. Again, TOR 60 and TAM 40 are statistically equivalent and the difference between TOR 240 and TAM 40 is not significant (P = 0.374). All treatments were well tolerated. As a conclusion TOR 60 and TAM 40 show equivalent clinical efficacy and tolerability. The higher dose of toremifene slightly but not significantly improved response rate and time to progression. In postmenopausal women, toremifene (60 mg) daily is an effective and safe treatment of advanced ER positive or ER unknown breast cancer.

We studied by indirect immunofluorescence microscopy the distribution of integrins and laminins in four human renal cell carcinoma cell lines (CAKI-2, A498, CAKI-1, and ACHN) in vitro and in s.c. xenografts in nude mice. In vitro, all four cell lines expressed the alpha 1, alpha 3, alpha v, beta 1, beta 3, and beta 5 subunits and three expressed the alpha 6 subunit; all cell lines expressed laminin A, B1, and B2 chains. Histologically, the CAKI-2 and A498 cells formed differentiated grade 1 (G1) and G2 tumors, respectively, while the CAKI-1 and ACHN cells formed poorly differentiated G3 tumors. The described integrin profile was largely retained upon xenografting. Basal polarization of the alpha 3 and alpha 6 integrin subunits was found in the differentiated tumors, and human laminins were detected as discrete linear structures surrounding tumor cell clusters in these tumors, suggesting that the cells have retained a polarized cell-laminin interaction characteristic of normal tubular epithelial cells. A disorganized distribution of integrins and laminins was noted in the G3 tumors. We conclude that these renal carcinoma cell lines displayed an integrin repertoire similar to that of clinical renal carcinomas and retained it upon xenografting. Furthermore, the organization of integrins and laminins in the xenografts correlated with histological grade.