bluuebunny/crossref_metadata_2025 huggingface dataset:
Histone deacetylase inhibitors induce growth arrest, apoptosis, and differentiation in clear cell sarcoma models
Authors: Liu Shuzhen , Cheng Hongwei , Kwan Wanda , Lubieniecka Joanna M. , Nielsen Torsten O.
Published: June 2008

Clear cell sarcoma is an aggressive malignancy occurring most commonly in the distal extremities of young adults, characterized by t(12;22)(q13;q12) creating the chimeric fusion oncoprotein EWS-ATF1. We assessed growth inhibition and differentiation effects of histone deacetylase inhibitors MS-275 and romidepsin (depsipeptide, FK228) on clear cell sarcoma cells and evaluated drug sensitivity among related translocation-associated sarcomas and other cell models. Three clear cell sarcoma cell lines, seven other sarcomas, six nonsarcoma malignant cell lines, and two nonneoplastic mesenchymal cell models were treated with MS-275 or romidepsin. Growth inhibition was assayed by monolayer 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Induction of cell cycle arrest and apoptosis were assessed by propidium iodide/Annexin V flow cytometry in monolayer and spheroid cultures and by immunoblotting analysis. Expression levels of key genes involved in mesenchymal differentiation and of EWS-ATF1 were measured by quantitative real-time PCR in clear cell sarcoma cells treated with histone deacetylase inhibitors. MS-275 and romidepsin inhibited growth in clear cell sarcoma cells by inducing cell cycle arrest and apoptosis in a time- and dose-dependent manner. Sarcomas showed greater sensitivity than other tumor types, with clear cell sarcomas most sensitive of all, whereas nonmalignant mesenchymal cells were highly resistant. MS-275 at 1 μmol/L and romidepsin at 1 nmol/L induced histone H3 acetylation, cell cycle arrest, apoptosis, and differentiation in clear cell sarcoma cells within 24 hours. Histone deacetylase inhibitors increased expression of SOX9, MYOD1, and PPARG and decreased EWS-ATF1 expression in clear cell sarcoma cells. Histone deacetylase inhibitors show promising preclinical activity in multiple clear cell sarcoma models. [Mol Cancer Ther 2008;7(6):1751–61]
Biodistribution and kinetics of the novel selective oncolytic adenovirus M1 after systemic administration
Authors: Huang Xiaoyuan , Zhuang Liang , Cao Yang , Gao Qinglei , Han Zhiqiang , Tang Duozhuang , Xing Hui , Wang Wei , Lu Yunping , Xu Gang , Wang Shixuan , Zhou Jianfeng , Ma Ding
Published: June 2008

Oncolytic adenoviruses represent a promising novel therapeutic option for the treatment of cancer. Despite their demonstrated safety in human clinical trials, the fundamental properties of oncolytic adenovirus biodistribution, spread, viral persistence, and replication in vivo have not been well characterized. The aim of this study was to evaluate the kinetics of viral distribution, spread, replication, and antitumoral efficacy after i.v. administration of a novel oncolytic mutant M1. This mutant consists of the E1A CR2-deleted Adv5 with a fragment of antisense polo-like kinase 1 (plk1) cDNA inserted into the deleted 6.7K/gp19K region, which combines oncolytic properties with efficient plk1 silencing, as described in our previous reports. In the present study, we established a new human orthotopic gastric carcinoma with a high frequency metastasis mouse model and showed that M1 spread not only in local primary tumors but also in disseminated metastases. M1 could effectively replicate in tumor cells leading to “oncolysis” and was able to eliminate expression of the targeted gene plk1 in human orthotopic gastric carcinoma model mice. Therefore, i.v. administration of M1 could prolong the survival time of tumor-bearing mice. [Mol Cancer Ther 2008;7(6):1624–32]
Arsenic trioxide decreases AKT protein in a caspase-dependent manner
Authors: Mann Koren K. , Colombo Myrian , Miller Wilson H.
Published: June 2008

Arsenic trioxide (As2O3) is used clinically to treat acute promyelocytic leukemia but is less successful in other malignancies. To identify targets for potential combination therapies, we have begun to characterize signaling pathways leading to As2O3-induced cytotoxicity. Previously, we described the requirement for a reactive oxygen species–mediated, SEK1/c-Jun NH2-terminal kinase (JNK) pathway to induce apoptosis. AKT inhibits several steps in this pathway; therefore, we postulated that As2O3 might decrease its activity. Indeed, As2O3 decreases not only AKT activity but also total AKT protein, and sensitivity to As2O3 correlates with the degree of AKT protein decrease. Decreased AKT expression further correlates with JNK activation and the release of AKT from the JNK-interacting protein 1 scaffold protein known to assemble the mitogen-activated protein kinase cascade. We found that As2O3 regulates AKT protein stability without significant effects on its transcription or translation. We show that As2O3 decreases AKT protein via caspase-mediated degradation, abrogated by caspase-6, caspase-8, caspase-9, and caspase-3 inhibitors but not proteosome inhibitors. Furthermore, As2O3 enhances the ability of a heat shock protein 90 inhibitor to decrease AKT expression and increase growth inhibition. This suggests that As2O3 may be useful in combination therapies that target AKT pathways or in tumors that have constitutively active AKT expression. [Mol Cancer Ther 2008;7(6):1680–7]
Emodin azide methyl anthraquinone derivative triggers mitochondrial-dependent cell apoptosis involving in caspase-8-mediated Bid cleavage
Authors: Yan Yanyan , Su Xiaodong , Liang Yongju , Zhang Jianye , Shi Chengjun , Lu Yu , Gu Lianquan , Fu Liwu
Published: June 2008

AMAD, an emodin azide methyl anthraquinone derivative, was extracted from the nature giant knotweed rhizome of traditional Chinese herbs. Here, we investigated the anticancer activities and signaling pathways implicated in AMAD-induced apoptosis in human breast cancer cell lines MDA-MB-453 and human lung adenocarcinoma Calu-3 cells. AMAD was found to have a potent cytotoxic effect on both cell lines. Hoechst 33258 staining and Annexin V/propidium iodide double staining exhibited the typical nuclear features of apoptosis and increased the proportion of apoptotic Annexin V–positive cells in a dose-dependent manner, respectively. Moreover, this apoptotic induction was associated with a collapse of the mitochondrial membrane potential and activated caspases (cysteine aspartase) cascade involving in caspase-8, caspase-9, caspase-3, and poly(ADP-ribose) polymerase cleavage in a concentration-dependent manner. It was noteworthy that AMAD also effectively cleaved Bid, a BH3 domain-containing proapoptotic Bcl-2 family member, and induced the subsequent release of cytochrome c from mitochondria into the cytosol. Furthermore, suppression of caspase-8 activity with Z-IETD-FMK partially inhibited release of cytochrome c and Bid cleavage induced by AMAD, whereas exposure to Z-LETD-FMK, a caspase-9 inhibitor, had no effect. Additionally, there was significant change in other mitochondrial membrane proteins triggered by AMAD, such as Bcl-xl and Bad. It was intriguing that AMAD decreased the generation of reactive oxygen species in both cell lines. DNA-binding assay exhibited apoptosis induced by AMAD was not involved in intercalating to DNA. Taken together, these data suggested that AMAD induced apoptosis via a mitochondrial pathway involving caspase-8/Bid activation in both cell lines. [Mol Cancer Ther 2008;7(6):1688–97]
Pinitol targets nuclear factor-κB activation pathway leading to inhibition of gene products associated with proliferation, apoptosis, invasion, and angiogenesis
Authors: Sethi Gautam , Ahn Kwang Seok , Sung Bokyung , Aggarwal Bharat B.
Published: June 2008

Pinitol (3-O-methyl-chiroinositol), a component of traditional Ayurvedic medicine (talisapatra), has been shown to exhibit anti-inflammatory and antidiabetic activities through undefined mechanisms. Because the transcription factor nuclear factor-κB (NF-κB) has been linked with inflammatory diseases, including insulin resistance, we hypothesized that pinitol must mediate its effects through modulation of NF-κB activation pathway. We found that pinitol suppressed NF-κB activation induced by inflammatory stimuli and carcinogens. This suppression was not specific to cell type. Besides inducible, pinitol also abrogated constitutive NF-κB activation noted in most tumor cells. The suppression of NF-κB activation by pinitol occurred through inhibition of the activation of IκBα kinase, leading to sequential suppression of IκBα phosphorylation, IκBα degradation, p65 phosphorylation, p65 nuclear translocation, and NF-κB-dependent reporter gene expression. Pinitol also suppressed the NF-κB reporter activity induced by tumor necrosis factor receptor (TNFR)-1, TNFR-associated death domain, TNFR-associated factor-2, transforming growth factor-β–activated kinase-1 (TAK-1)/TAK1-binding protein-1, and IκBα kinase but not that induced by p65. The inhibition of NF-κB activation thereby led to down-regulation of gene products involved in inflammation (cyclooxygenase-2), proliferation (cyclin D1 and c-myc), invasion (matrix metalloproteinase-9), angiogenesis (vascular endothelial growth factor), and cell survival (cIAP1, cIAP2, X-linked inhibitor apoptosis protein, Bcl-2, and Bcl-xL). Suppression of these gene products by pinitol enhanced the apoptosis induced by TNF and chemotherapeutic agents and suppressed TNF-induced cellular invasion. Our results show that pinitol inhibits the NF-κB activation pathway, which may explain its ability to suppress inflammatory cellular responses. [Mol Cancer Ther 2008;7(6):1604–14]
Human α-defensin-1 inhibits growth of human lung adenocarcinoma xenograft in nude mice
Authors: Xu Ning , Wang Yong-sheng , Pan Wu-bin , Xiao Bo , Wen Yan-jun , Chen Xian-cheng , Chen Li-juan , Deng Hong-xin , You Jia , Kan Bing , Fu A-fu , Li Dan , Zhao Xia , Wei Yu-quan
Published: June 2008

Human α-defensin-1 (HNP1), a small antimicrobial peptide, shows cytotoxicity to tumor cells in vitro and inhibitory activity for pathologic neovascularization in vivo. Here, we did a gene therapy with a plasmid that expresses a secretable form of HNP1 for assaying its antitumor activity. The expression and secretion of HNP1 were determined by reverse transcription-PCR and ELISA in vitro. We found that expression of HNP1 in A549 tumor cells caused significant growth inhibition. This effect is most likely cell autonomous, as a significant amount of recombinant HNP1 protein was found to be accumulated in the cytoplasm by immunohistochemical staining using an anti-HNP1 antibody and the supernatant containing secreted HNP1 failed to produce any noticeable antitumor activity. Flow cytometry and Hoechst 33258 staining showed that the number of apoptotic cells among the A549 cells expressing recombinant HNP1 proteins was significantly greater than that of the nontransfected control cultures, suggesting that this growth-inhibitory activity was due to an apoptotic mechanism triggered by the intracellular HNP1. The antitumor activity of intracellularly expressed HNP1 was also shown in vivo. Decreased microvessel density and increased lymphocyte infiltration were observed in tumor tissue from HNP1-treated mice through histologic analysis. These results indicate that intracellularly expressed HNP1 induces tumor cell apoptosis, which inhibits tumor growth. The antiangiogenesis effect of HNP1 may contribute to its inhibitory activity in vivo, and HNP1 might involve the host immune response to tumor. These findings provide a rationale for developing HNP1-based gene therapy for cancer. [Mol Cancer Ther 2008;7(6):1588–97]
Trichostatin A up-regulates p73 and induces Bax-dependent apoptosis in cisplatin-resistant ovarian cancer cells
Authors: Muscolini Michela , Cianfrocca Roberta , Sajeva Angela , Mozzetti Simona , Ferrandina Gabriella , Costanzo Antonio , Tuosto Loretta
Published: June 2008

Several studies in the last years evidenced that deregulation of proapoptotic and antiapoptotic pathways are key players in the onset and maintenance of chemoresistance in advanced ovarian cancers. To characterize the signaling events and molecules involved in the acquisition of cisplatin resistance, we used the human ovarian cancer cell line A2780 and its derivative cisplatin-resistant subline A2780 CIS. We found that the mitochondrial intrinsic apoptotic pathway, induced by cis-dichlorodiammineplatinum (CDDP) in A2780 wild-type cells, was compromised in the resistant subline CIS. The analysis of expression of proteins involved in mitochondria-dependent apoptosis revealed a role of Bax and p73 but not p53. Indeed, we found that CDDP treatment induced the up-regulation of p53 in both sensitive and resistant A2780 cell lines. By contrast, p73 and Bax expressions were compromised in resistant cells. Pretreatment of resistant A2780 CIS cells with the histone deacetylase inhibitor trichostatin A overcomes apoptosis resistance to CDDP by restoring both p73 and Bax but not p53 expression. Altogether, these data indicate that p73, but not p53, is involved in the regulation of apoptosis susceptibility to cisplatin in A2780 ovarian cancer cells and evidence a key contribution of histone deacetylase activation in the acquisition of chemotherapy resistance in human ovarian cancer cells. [Mol Cancer Ther 2008;7(6):1410–9]
Gene Therapy in Heart Failure
Authors: Vinge Leif Erik , Raake Philip W. , Koch Walter J.
Published: June 2008

With increasing knowledge of basic molecular mechanisms governing the development of heart failure (HF), the possibility of specifically targeting key pathological players is evolving. Technology allowing for efficient in vivo transduction of myocardial tissue with long-term expression of a transgene enables translation of basic mechanistic knowledge into potential gene therapy approaches. Gene therapy in HF is in its infancy clinically with the predominant amount of experience being from animal models. Nevertheless, this challenging and promising field is gaining momentum as recent preclinical studies in larger animals have been carried out and, importantly, there are 2 newly initiated phase I clinical trials for HF gene therapy. To put it simply, 2 parameters are needed for achieving success with HF gene therapy: (1) clearly identified detrimental/beneficial molecular targets; and (2) the means to manipulate these targets at a molecular level in a sufficient number of cardiac cells. However, several obstacles do exist on our way to efficient and safe gene transfer to human myocardium. Some of these obstacles are discussed in this review; however, it primarily focuses on the molecular target systems that have been subjected to intense investigation over the last decade in an attempt to make gene therapy for human HF a reality.
Quantitative Estimates of the Economic Impacts of a Korea–United States Free Trade Agreement
Authors: Lee Hongshik , Song Backhoon
Published: June 2008

This paper investigates the bilateral trade pattern between South Korea and the United States and examines the economic impact of a Korea–United States (KORUS) free trade agreement (FTA). Three related general equilibrium approaches were used to investigate the effects of a KORUS FTA. The static general equilibrium model estimates the efficiency gains from resource allocation. The capital accumulation general equilibrium model includes the growth bonus from the increased incentives for savings and investment created by the static efficiency gains. The productivity enhancement general equilibrium model augments the capital accumulation model by taking into consideration the dynamic efficiency improvements from competitive effects in the economies over time. The last welfare gain turns out to be the biggest gain from the KORUS FTA, dwarfing the static efficiency gains. The results indicate that Korea could gain an estimated 0.32 to 5.97 percent in GDP from a KORUS FTA. Much of the gains that would accrue to Korea from the FTA with the United States would be productivity gains from increased competition between U.S. producers and domestic Korean producers. Another important area of gain for Korea would be increased efficiency from lower non-tariff barriers. This provides a strong argument for ensuring that an FTA between Korea and the United States is comprehensive and facilitates regulatory cooperation and the reduction of non-tariff barriers.
Intermodal Auditory, Visual, and Tactile Attention Modulates Early Stages of Neural Processing
Authors: Karns Christina M. , Knight Robert T.
Published: June 2008

We used event-related potentials (ERPs) and gamma band oscillatory responses (GBRs) to examine whether intermodal attention operates early in the auditory, visual, and tactile modalities. To control for the effects of spatial attention, we spatially coregistered all stimuli and varied the attended modality across counterbalanced blocks in an intermodal selection task. In each block, participants selectively responded to either auditory, visual, or vibrotactile stimuli from the stream of intermodal events. Auditory and visual ERPs were modulated at the latencies of early cortical processing, but attention manifested later for tactile ERPs. For ERPs, auditory processing was modulated at the latency of the Na (29 msec), which indexes early cortical or thalamocortical processing and the subsequent P1 (90 msec) ERP components. Visual processing was modulated at the latency of the early phase of the C1 (62–72 msec) thought to be generated in the primary visual cortex and the subsequent P1 and N1 (176 msec). Tactile processing was modulated at the latency of the N160 (165 msec) likely generated in the secondary association cortex. Intermodal attention enhanced early sensory GBRs for all three modalities: auditory (onset 57 msec), visual (onset 47 msec), and tactile (onset 27 msec). Together, these results suggest that intermodal attention enhances neural processing relatively early in the sensory stream independent from differential effects of spatial and intramodal selective attention.
On Why Left Events are the Right Ones: Neural Mechanisms Underlying the Left-hemifield Advantage in Rapid Serial Visual Presentation
Authors: Verleger Rolf , Sprenger Andreas , Gebauer Sina , Fritzmannova Michaela , Friedrich Monique , Kraft Stefanie , Jaśkowski Piotr
Published: June 2008

When simultaneous series of stimuli are rapidly presented left and right, containing two target stimuli T1 and T2, T2 is much better identified when presented in the left than in the right hemifield. Here, this effect was replicated, even when shifts of gaze were controlled, and was only partially compensated when T1 side provided the cue where to expect T2. Electrophysiological measurement revealed earlier latencies of T1- and T2-evoked N2pc peaks at the right than at the left visual cortex, and larger right-hemisphere T2-evoked N2pc amplitudes when T2 closely followed T1. These findings suggest that the right hemisphere was better able to single out the targets in time. Further, sustained contralateral slow shifts remained active after T1 for longer time at the right than at the left visual cortex, and developed more consistently at the right visual cortex when expecting T2 on the contralateral side. These findings might reflect better capacity of right-hemisphere visual working memory. These findings about the neurophysiological underpinnings of the large right-hemisphere advantage in this complex visual task might help elucidating the mechanisms responsible for the severe disturbance of hemineglect following damage to the right hemisphere.
Kynurenine pathway in psychosis: evidence of increased tryptophan degradation
Authors: Barry S , Clarke G , Scully P , Dinan TG
Published: June 2008

Abstract

The kynurenine pathway of tryptophan degradation may serve to integrate disparate abnormalities heretofore identified in research aiming to elucidate the complex aetiopathogenesis of psychotic disorders. Post-mortem brain tissue studies have reported elevated kynurenine and kynurenic acid in the frontal cortex and upregulation of the first step of the pathway in the anterior cingulate cortex of individuals with schizophrenia. In this study, we examined kynurenine pathway activity by measuring tryptophan breakdown, a number of pathway metabolites and interferon gamma (IFN-γ), which is the preferential activator of the first-step enzyme, indoleamine dioxygenase (IDO), in the plasma of patients with major psychotic disorder. Plasma tryptophan, kynurenine pathway metabolites were measured using high-performance liquid chromatography (HPLC) in 34 patients with a diagnosis on the psychotic spectrum (schizophrenia or schizoaffective disorder) and in 36 healthy control subjects. IFN-γ was measured using enzyme-linked immunosorbent assay (ELISA). The mean tryptophan breakdown index (kynurenine/tryptophan) was significantly higher in the patient group compared with controls ( P < 0.05). IFN-γ measures did not differ between groups ( P = 0.23). No relationship was found between measures of psychopathology, symptom severity and activity in the first step in the pathway. A modest correlation was established between the tryptophan breakdown index and illness duration. These results provide evidence for kynurenine pathway upregulation, specifically involving the first enzymatic step, in patients with major psychotic disorder. Increased tryptophan degradation in psychoses may have potential consequences for the treatment of these disorders by informing the development of novel therapeutic compounds.
Efficacy and tolerability of ziprasidone versus risperidone as augmentation in patients partially responsive to clozapine: a randomised controlled clinical trial
Authors: Zink M , Kuwilsky A , Krumm B , Dressing H
Published: June 2008

Abstract

Patients suffering from schizophrenic psychoses sometimes insufficiently respond to antipsychotic monotherapy and then combination approaches are preferred. We aimed in validating the add-on of ziprasidone and risperidone to clozapine, and we performed a randomised head-to-head trial. Patients with partial response to clozapine were randomly attributed to augmentation with ziprasidone ( n = 12) or risperidone ( n = 12). Efficacy assessments included the Positive and Negative Syndrome Scale (PANSS), the Scale for the Assessment of Negative Symptoms (SANS), the Hamilton Depression Scale (HAMD), the Clinical Global Impression (CGI) and the Global Assessment of Functioning (GAF). Furthermore, several safety and tolerability measures were obtained. After six weeks, both groups showed significant reductions of positive and negative symptoms. In addition, affective state, psychosocial functioning and clozapine side effects improved without significant differences between the groups. Both approaches were well tolerated. However, the ziprasidone group experienced a small elongation of the QTc interval and a reduction of extrapyramidal symptoms. Patients under clozapine–risperidone therapy developed a rise of serum prolactin levels. The clozapine augmentation with ziprasidone or risperidone resulted in significant psychopathological improvements. The side effects differed between the treatment groups. Further head-to-head comparisons of atypical antipsychotics as add-on to clozapine are necessary.
Anhedonia and activity deficits in rats: impact of post-stroke depression
Authors: Wang SH , Zhang ZJ , Guo YJ , Zhou H , Teng GJ , Chen BA
Published: June 2008

Abstract

Animal models may allow investigation into the aetiology and treatment of various human disorders. In the present study, a rat model for post-stroke depression (PSD) has been developed using middle cerebral artery occlusion (MCAO), followed by an 18-day chronic mild stress (CMS) paradigm in conjuncture with isolation rearing. The open-field test (OFT) and the sucrose consumption test were used to assess depression-like behaviour and the effects of the antidepressant citalopram. CMS induced behavioural changes in the ischemic animals, including decreased locomotor and rearing activity and reduced sucrose preference (compared with baseline, control and stroke groups respectively), all these behaviours were reversed by chronic administration of citalopram. During the recovery period for the PSD models, the open-field activity and preference for sweet sucrose solution decreased continually, opposed to rats subjected to stress only. Decreased locomotor and rearing represents activity deficits, whereas reduced sucrose preference may indicate desensitisation of the brain reward mechanism (anhedonia). Our findings suggest that anhedonia, one of the core symptoms in patients with PSD, and activity deficits can be found in the MCAO+CMS group of animals. Furthermore, citalopram can ameliorate the behavioural abnormalities observed in these animals. With high validity, good operability and repeatability, our findings suggest that the ischemic rat CMS model is an appropriate model for further PSD research.
Effect of antidepressants on melatonin metabolite in depressed patients
Authors: Carvalho LA , Gorenstein C , Moreno R , Pariante C , Markus RP
Published: June 2008

Abstract

Antidepressants increase melatonin levels, but it is still unclear whether this effect is related to the improvement of depressive symptoms or to unrelated pharmacological action of antidepressants. To answer this question, the effect of antidepressants on 6-sulphatoxymelatonin (aMT6s), the main melatonin urinary metabolite, was examined in drug-free depressed patients – most of them antidepressant-naive. aMT6s was evaluated in 34 depressed patients, before and after 8 weeks of placebo ( n = 12) or antidepressant ( n = 22; fluoxetine, duloxetine or Hypericum perforatum). Both groups showed an improvement of depressive symptoms after treatment compared to baseline (Hamilton Depression scores): 17.0 ± 1.4 vs. 9.0 ± 2.8, P = 0.007 for placebo, and 18.6 ± 1.1 vs. 11.8 ± 1.6, P < 0.001 for antidepressants). After treatment, aMT6s levels increased after antidepressants ( P < 0.01), but not after placebo ( P > 0.05). As depressive symptoms improved both in patients taking antidepressant and in those taking placebo, but an effect of antidepressants could only be seen in those taking antidepressants, we suggest that melatonin changes after antidepressants are more likely due to a pharmacological action of these drugs on melatonin secretion.
Efficacy, tolerability and side-effect profile of fluvoxamine for major depression: meta-analysis
Authors: Omori IM , Watanabe N , Nakagawa A , Akechi T , Cipriani A , Barbui C , McGuire H , Churchill R , Furukawa TA
Published: June 2008

Abstract

Fluvoxamine, one of the oldest selective serotonin reuptaking inhibitors, is commonly prescribed to patients with major depression. Several studies have reviewed the efficacy and tolerability of fluvoxamine for the treatment of major depression. However, these reviews are outdated, have not been systematic and/or suffered from several methodological weaknesses. We conducted a systematic review to synthesize the best available evidence on the efficacy of fluvoxamine for adult patients suffering from major depression in comparison with other active antidepressive agents. Relevant randomized controlled trials were identified through a comprehensive search. The primary outcome was a relative risk of response, and the secondary outcome was a relative risk of remission. Tolerability and side-effect profile were also examined. Fifty-three trials were included. There were no large differences between fluvoxamine and any other antidepressants in terms of efficacy and tolerability. There is evidence of differing side effect profiles, especially when comparing gastrointestinal side effects between fluvoxamine and tricyclics. Clinicians should focus on practically or clinically relevant differences including those in side-effect profiles.
Hyperprolactinemia and possibly related development of prolactinoma during amisulpride treatment; three cases
Authors: Akkaya C , Kaya B , Kotan Z , Sarandol A , Ersoy C , Kirli S
Published: June 2008

Abstract

Schizophrenia is a chronic and debilitating psychotic mental disorder that affects about 1% of the world's population. Antipsychotic drugs are the mainstay of treatment in schizophrenia. Hyperprolactinemia, which is a common side effect of typical antipsychotics, is also associated with the use of some of the newer atypical agents. Antipsychotics may enhance prolactinoma growth as manifested by an increase in serum prolactin concentration. Prolactin-secreting pituitary adenomas possibly related with antipsychotics have been described in the literature. To our knowledge, this is the first series of cases showing a possible relation between pituitary adenomas and amisulpride treatment in patients with schizophrenia.
The addiction Stroop task: examining the fast and slow effects of smoking and marijuana-related cues
Authors: Cane JE , Sharma D , Albery IP
Published: June 2008

Abstract

Research has shown that attentional bias toward smoking-related stimuli is related to the maintenance of smoking behaviour and the chance of a relapse during a quit attempt. Effects of smoking attentional bias can occur both during smoking stimulus presentation (fast effect) and on stimuli that immediately follow smoking stimuli (slow effect). The current research builds on these findings by closely examining the temporal aspects of these fast and slow effects across groups of different smoking status. In Experiment 1 ( n = 64), smokers, smokers attempting to quit (SATQ) and non-smokers completed an addiction Stroop task using smoking related, negative emotion and neutral stimuli. In Experiment 2 ( n = 32), marijuana smokers and non-marijuana smokers completed an addiction Stroop task using marijuana and neutral stimuli. Results showed fast effects across all smoking groups (except non-smokers) and slow effects in SATQ and marijuana smokers. Furthermore, marijuana smokers showed slow effects over extended periods of time. Results also show a relationship between anxiety, nicotine dependence and attentional bias in SATQ. The implications of these findings are discussed.
Restless legs syndrome and periodic limb movements during sleep probably associated with olanzapine
Authors: Kang Seung-Gul , Lee Heon-Jeong , Kim Leen
Published: June 2008

Abstract

We report five cases of restless legs syndrome (RLS) and periodic limb movements during sleep (PLMS) that were probably associated with olanzapine. The first patient showed a good response to olanzapine, but the RLS symptoms associated with olanzapine resulted in poor long-term compliance, eventually leading to frequent relapse of psychotic symptoms. The second patient exhibited sudden PLMS following olanzapine injection. The third patient had been suffering from serious akathisia while on risperidone, and was cured after switching to olanzapine, but thereafter the patient suffered from RLS at nighttime. The fourth patient showed RLS symptoms that were initially caused by a 20-mg daily olanzapine dosage and were later mitigated when olanzapine was reduced and ropinirole was administered. The fifth patient exhibited paraesthesia and agitation caused by olanzapine that was misdiagnosed as psychotic agitation. Increasing the olanzapine dosage severely aggravated the symptoms of RLS. Antipsychotic-induced RLS and PLMS are not well-recognized side effects of antipsychotics, with the symptoms often misdiagnosed as psychotic agitation. These cases also suggest that the occurrence of RLS can cause noncompliance with antipsychotics in psychiatric patients, and thus aggravate their psychotic symptoms.
An experimental study of aggressive and neutral interpretative bias in opiate-dependent and opiate-abstinent men
Authors: Clair J , Martin L , Bond AJ , O’Ryan D , Davis P , Curran HV
Published: June 2008

Abstract

There is a paucity of research on the relationship between opiate use and aggression, and no previous study has examined this from a cognitive theoretical perspective, which views an individual’s interpretation of information as a central mediator of their response to it. This study aimed to determine whether opiate users and ex-users differed from opiate-naïve controls on a task which involved processing ambiguous sentences. In an independent group design, the interpretative bias task was administered to 64 participants: 21 opiate-dependent receiving methadone maintenance treatment, 21 opiate-abstinent in rehabilitation, and 22 healthy unemployed controls. We found that both opiate-dependent and opiate-abstinent groups interpreted ambiguous sentences in a neutral rather than an aggressive way, whereas controls showed no bias in either direction. In the opiate-dependent group, neutral interpretative bias correlated both with their current dose of methadone and years of methadone use. These findings indicate that current and ex-opiate users in treatment have a bias towards neutral interpretations of ambiguous information. The fact that neutral interpretative bias in opiate-dependent individuals correlated with current dose and years of methadone use suggests that methadone treatment is associated with a neutral cognitive bias. Decreased testosterone levels associated with chronic opiate use may underpin this neutral bias.
Policy Parallels
Authors: Getha-Taylor Heather
Published: June 2008

The 1978 Civil Service Reform Act may be considered President Carter's most impressive domestic political victory. This victory can be linked to the efforts of many, but specifically to Alan K. (Scotty) Campbell, who served as the chief architect of the legislation and began implementing the act as first director of the U.S. Office of Personnel Management. Thirty years later, personnel reform is again a presidential priority. As part of the 2002 Homeland Security Act, the Bush administration introduced provisions to enhance flexibility and performance, yet the contemporary reforms met considerable resistance. In an effort to compare and contrast these two reform efforts, this article draws upon historical evidence to examine how Campbell effectively engaged diverse stakeholders in the policy design process, why he championed performance-based pay, and how as a political appointee, he guided lasting change on the federal level.
Effects of melatonin and vitamin C on cigarette smoke–induced damage in the kidney
Authors: Ozan E , Sonmez MF , Ozan S , Colakoglu N , Yilmaz S , Kuloglu T
Published: June 2008

This study was carried out to investigate smoke-induced structural and biochemical changes and protective effects of co-administered melatonin and vitamin C in the kidney. Twenty-four Wistar adult female rats were used in this study. Animals were divided into four groups. The first group rats were used as control. The second group of rats inhaled cigarette smoke. Smile smoke inhaling third and fourth group rats received melatonin and vitamin C, respectively. At the end of experimental study, kidney tissues and blood samples were taken under ether anesthesia. Tissues were prepared and examined by light microscopy. Malondialdehyde and glutathione levels and catalase activity were determined. By light microscopic observation, a decrease of Bowman space of some renal corpuscles, foamy-like tubules, dilatation and congestion of the peritubuler vessels, and atrophy of the some renal corpuscles were observed in group II. In groups III and IV melatonin and vitamin C relatively protected the kidney tissue against smoke intoxication. Biochemical examination showed that malondialdehyde and glutathione levels and catalase activity in group II were higher than in group I. Melatonin and vitamin C injection to group III and IV caused a decrease in malondialdehyde and glutathione levels. Catalase activity did not change in these groups. We have shown that cigarette smoke inhalation caused structural changes in the kidney. However, melatonin and vitamin C administration produced in some degree protection against smoke-induced damage.
Heavy metals other than lead in flaked paints from buildings in Eastern Nigeria
Authors: Nduka JKC , Orisakwe OE , Maduawguna CA
Published: June 2008

Cadmium, chromium, iron, zinc, and copper levels of flaked paints collected from fifty buildings of four major cities – Enugu, Onitsha, Aba, and Port Harcourt in Eastern Nigeria were studied. Fifty samples of the flaked paints were ground with laboratory pestle and mortar, 2 g of fine ground paints that could pass through a 0.5-mm sieve were digested with 15 ml concentrated nitric acid and perchloric acid at a ratio of 1:1 and analyzed for cadmium, chromium, iron, zinc and copper using atomic absorption spectrophotometer 500. Cadmium ranged from 9.032 ± 0.000 to 10.575± 0.000 and 6.845 ± 0.000 to 10.028 ± 0.002 mg/kg in Enugu and Onitsha, respectively. In Aba and Port Harcourt, the levels of cadmium ranged 7.464 ± 0.002–9.343 ± 0.002 and 7.293 ± 0.002–9.395 ± 0.000 mg/kg, respectively. Chromium levels were significantly lower in Enugu (range 0.940 ± 0.000–12.793 ± 0.002 mg/kg) when compared with the values from other cities namely Onitsha (range 1.613 ± 0.002–15.140 ± 0.000 mg/kg), Aba (range 15.206 ± 0.000–39.215 ± 0.000 mg/kg) and Port Harcourt (range 33.118 ± 0.002–55.418 ± 0.002 mg/kg). The highest levels (mg/kg) of iron (11 908.150 ± 0.000), zinc (31.508 ± 0.002) and copper (7.588 ± 0.002) were seen in buildings from Enugu aged 11 years and above. The iron level (mg/kg) ranged from 1391.750 ± 0.000 to 10 476.845 ± 0.000, 1450.176 ± 0.000 to 11 580.750 ± 0.000 and 3314.913 ± 0.002 to 8162.333 ± 0.002 in Onitsha, Aba, and Port Harcourt, respectively. Zinc levels were significantly lower in Onitsha than in Aba and Port Harcourt. Age of building did not seem to affect the levels of these metals namely iron, zinc and copper from these cities. This study shows that flaked paints increase the environmental heavy metal burden in Nigeria.
Multi-state models for the analysis of time-to-event data
Authors: Meira-Machado Luís , de Uña-Álvarez Jacobo , Cadarso-Suárez Carmen , Andersen Per K
Published: June 2008

The experience of a patient in a survival study may be modelled as a process with two states and one possible transition from an “alive” state to a “dead” state. In some studies, however, the “alive” state may be partitioned into two or more intermediate (transient) states, each of which corresponding to a particular stage of the illness. In such studies, multi-state models can be used to model the movement of patients among the various states. In these models issues, of interest include the estimation of progression rates, assessing the effects of individual risk factors, survival rates or prognostic forecasting. In this article, we review modelling approaches for multi-state models, and we focus on the estimation of quantities such as the transition probabilities and survival probabilities. Differences between these approaches are discussed, focussing on possible advantages and disadvantages for each method. We also review the existing software currently available to fit the various models and present new software developed in the form of an R library to analyse such models. Different approaches and software are illustrated using data from the Stanford heart transplant study and data from a study on breast cancer conducted in Galicia, Spain.
Meta-analyses of safety data: a comparison of exact versus asymptotic methods
Authors: Vandermeer Ben , Bialy Liza , Hooton Nicola , Hartling Lisa , Klassen Terry P , Johnston Bradley C , Wiebe Natasha
Published: June 2008

The objectives of this study were to establish and describe a database of Cochrane and non-Cochrane meta-analyses of safety data and to determine under what conditions exact methods differ from asymptotic methods in meta-analyses of safety data. A sample of Cochrane ( n = 500) and non-Cochrane ( n = 200) systematic reviews was randomly selected and a database of safety meta-analyses established. Point estimates and confidence intervals for each meta-analysis were recalculated using exact methods and compared to the results of asymptotic methods. Cochrane reviews were nearly four times as likely as non-Cochrane reviews to contain meta-analyses of safety data (35% compared to 9%). More than 50% of safety meta-analyses contained an outcome with a rare event rate ( <5%) and 30% contained at least one study with no events in one arm of the study. For rare event meta-analyses, exact point estimates differed substantially from asymptotic estimates 46% of the time, compared to 17% for those without rare events. Exact confidence intervals differed substantially from asymptotic ones 67% of the time compared to only 19% for those without rare events. The magnitude of differences was also correlated with the number of studies and the summary statistic used to combine the data. Asymptotic methods will not always be a good approximation for exact methods in safety meta-analyses. Event rates and number of studies should be closely examined when choosing the statistical method for combining rare event data.
Student Identification With Business Education Models
Authors: Halbesleben Jonathon R. B. , Wheeler Anthony R.
Published: June 2008

Although management scholars have provided a variety of metaphors to describe the role of students in management courses, researchers have yet to explore students' identification with the models and how they are linked to educational outcomes. This article develops a measurement tool for students' identification with business education models and explores how those identifications are related to educational outcomes. In two samples of undergraduate management students ( N = 916), the authors developed and validated a Student Identification With Business Education Models scale and found links between specific models and grade point average, course satisfaction, likelihood to donate to the university or college, and perceived discrepancy between current and deserved course grade. The authors discuss the implications of the findings in the context of management education innovations to improve student outcomes.
Informing Child Welfare Policy and Practice
Authors: Duncan Dean F. , Kum Hye-Chung , Caplick Weigensberg Elizabeth , Flair Kimberly A. , Stewart C. Joy
Published: June 2008

Proper management and implementation of an effective child welfare agency requires the constant use of information about the experiences and outcomes of children involved in the system, emphasizing the need for comprehensive, timely, and accurate data. In the past 20 years, there have been many advances in technology that can maximize the potential of administrative data to promote better evaluation and management in the field of child welfare. Specifically, this article discusses the use of knowledge discovery and data mining (KDD), which makes it possible to create longitudinal data files from administrative data sources, extract valuable knowledge, and make the information available via a user-friendly public Web site. This article demonstrates a successful project in North Carolina where knowledge discovery and data mining technology was used to develop a comprehensive set of child welfare outcomes available through a public Web site to facilitate information sharing of child welfare data to improve policy and practice.
Disease-modifying agents in the Sonya Slifka Longitudinal Multiple Sclerosis Study
Authors: Minden S , Hoaglin D , Jureidini S , Hadden L , Frankel D , Komatsuzaki Y , Outley J
Published: June 2008

Background

Although experts recommend that people with multiple sclerosis (MS) should begin treatment with disease-modifying agents (DMAs) as soon as possible after diagnosis and continue indefinitely, many do not use these agents or discontinue them prematurely. Since DMAs reduce relapse rates and slow disease progression, and since even benign relapses and course can lead to axonal damage and permanent neurologic impairment, it is important that all appropriate candidates have access to treatment. We used a population-based sample of people with MS to determine rates, predictors, and reasons for use, non-use, and discontinuation of DMAs.

Methods

We collected data from 2156 people with MS on their use of and experience with DMAs. We used chi-squared tests to compare current, past, and never users of any DMA and ever users of individual DMAs, and logistic regression to identify predictors of use.

Results

One-half of the participants were using a DMA at the time of the interview; 12.2% had used previously, but stopped. Reasons for never using and reasons for stopping were at odds with expert recommendations. Characterization of users, and of their experiences by type of DMA, was consistent with current knowledge of these agents. Seeing a neurologist for usual MS care was an important factor in starting and persisting with DMA therapy.

Conclusions

Dissemination of expert opinion about, and management strategies for, use of DMAs to non-neurologic professionals and patients and their families might help more people who are appropriate candidates for DMA therapy to start and continue treatment.
Paradoxically aggressive multiple sclerosis in the face of natalizumab therapy
Authors: Berger JR
Published: June 2008

In the pivotal trials of natalizumab in the treatment of relapsing-remitting multiple sclerosis (AFFIRM and SENTINEL), a dramatic reduction in relapse rate, new or enlarging T2-hyperintense lesions, and mean number of gadolinium-enhancing lesions was observed. While both relapses and new MRI lesions were observed in these trials, there has been no comment on the presence of aggressive disease in the face of natalizumab treatment. I report a 31-year-old woman with relapsing remitting MS of 12 years duration who developed aggressive demyelinating disease four months after the initiation of natalizumab. The clinical worsening was accompanied by a significant increase in new large T2-hyperintense signal abnormalities and in both solid and C-shaped contrast-enhancing lesions. Neither the clinical severity nor the striking MRI abnormalities had been noted earlier in her disease course. Neutralizing antibodies to natalizumab were not detected. She subsequently responded to combination therapy of pulsed methylprednisolone and daily glatiramer acetate.
Expression of the inhibitor of apoptosis protein family in multiple sclerosis reveals a potential immunomodulatory role during autoimmune mediated demyelination
Authors: Hebb ALO , Moore CS , Bhan V , Campbell T , Fisk JD , Robertson HA , Thorne M , Lacasse E , Holcik M , Gillard J , Crocker SJ , Robertson GS
Published: June 2008

A failure of autoreactive T cells to undergo apoptosis may contribute to the pathogenesis of multiple sclerosis (MS). The role of the inhibitor of apoptosis (IAP) family of anti-apoptotic proteins such as X-linked IAP (XIAP), human inhibitor of apoptosis-1 (HIAP-1), human inhibitor of apoptosis-2 (HIAP-2), neuronal apoptosis inhibitory protein (NAIP) and Survivin in relapsing–remitting, secondary-progressive, primary-progressive or benign forms of MS is unclear. We report here that expression of the IAP family of genes in peripheral blood samples and brain tissues from MS cases support a role for differential regulation of these potent anti-apoptotic proteins in the pathology of MS. XIAP mRNA and protein levels were elevated in peripheral blood mononuclear cells from patients with active disease relative to normal subjects. In patients with active MS, HIAP-1 and HIAP-2 mRNA levels were elevated in resting T cells while NAIP mRNA was increased in whole blood. In post-mortem MS brain tissue, XIAP and HIAP-1 in myelin lesions were co-localized with microglia and T cells, respectively. Only in primary-progressive patients was Survivin expression elevated suggestive of a distinct pathological basis for this subtype of MS. Taken together, these results suggest that patterns of inhibitor of apoptosis expression in immune cells may have value in distinguishing between MS subtypes and offer insight into the mechanisms responsible for their distinct clinical courses.