bluuebunny/crossref_metadata_2025 huggingface dataset:
Interleukin-1β, but not interleukin-6, enhances renal and systemic endothelin production in vivo
Authors: Boesen Erika I. , Sasser Jennifer M. , Saleh Mohamed A. , Potter William A. , Woods Mandy , Warner Timothy D. , Pollock Jennifer S. , Pollock David M.
Published: June 2008

The inflammatory cytokines IL-1β and IL-6 have been shown to stimulate production of endothelin-1 (ET-1) by several cell types in vitro, but their effects on renal ET-1 production in vivo are not known. To test whether IL-1β and IL-6 stimulate renal ET-1 production and release in vivo, urine was collected from male C57BL/6 mice over 24-h periods at baseline and on days 7 and 14 of a 14-day subcutaneous infusion of IL-1β (10 ng/h), IL-6 (16 ng/h), or vehicle. By day 14, plasma ET-1 was significantly increased by IL-1β infusion (1.7 ± 0.1 vs. 0.8 ± 0.1 pg/ml for vehicle, P < 0.001). Compared with vehicle infusion, IL-1β infusion induced significant increases in urinary ET-1 excretion rate and urine flow but did not affect conscious mean arterial pressure (telemetry). IL-1β infusion significantly increased renal cortical and medullary IL-1β content (ELISA) and prepro-ET-1 mRNA expression (quantitative real-time PCR). In contrast, 14 days of IL-6 infusion had no significant effect on plasma ET-1 or urinary ET-1 excretion rate. To determine whether IL-1β stimulates ET-1 release via activation of NF-κB, inner medullary collecting duct (IMCD-3) cells were incubated for 24 h with IL-1β, and ET-1 release and NF-κB activation were measured (ELISA). IL-1β activated NF-κB and increased ET-1 release in a concentration-dependent manner. The effect of IL-1β on ET-1 release could be partially inhibited by pretreatment of IMCD-3 cells with an inhibitor of NF-κB activation (BAY 11-7082). These results indicate that IL-1β stimulates renal and systemic ET-1 production in vivo, providing further evidence that ET-1 participates in inflammatory responses.
G-Quadruplex Stabilizer 3,6-Bis(1-Methyl-4-Vinylpyridinium)Carbazole Diiodide Induces Accelerated Senescence and Inhibits Tumorigenic Properties in Cancer Cells
Authors: Huang Fong-Chun , Chang Cheng-Chung , Lou Pei-Jen , Kuo I-Chun , Chien Chih-Wei , Chen Chin-Tin , Shieh Fu-Ying , Chang Ta-Chau , Lin Jing-Jer
Published: May 2008

Carbazole derivatives that stabilized G-quadruplex DNA structure formed by human telomeric sequence have been designed and synthesized. Among them, 3,6-bis(1-methyl-4-vinylpyridinium)carbazole diiodide (BMVC) showed an increase in G-quadruplex melting temperature by 13°C and has a potent inhibitory effect on telomerase activity. Treatment of H1299 cancer cells with 0.5 μmol/L BMVC did not cause acute toxicity and affect DNA replication; however, the BMVC-treated cells ceased to divide after a lag period. Hallmarks of senescence, including morphologic changes, detection of senescence-associated β-galactosidase activity, and decreased bromodeoxyuridine incorporation, were detected in BMVC-treated cancer cells. The BMVC-induced senescence phenotype is accompanied by progressive telomere shortening and detection of the DNA damage foci, indicating that BMVC caused telomere uncapping after long-term treatments. Unlike other telomerase inhibitors, the BMVC-treated cancer cells showed a fast telomere shortening rate and a lag period of growth before entering senescence. Interestingly, BMVC also suppressed the tumor-related properties of cancer cells, including cell migration, colony-forming ability, and anchorage-independent growth, indicating that the cellular effects of BMVC were not limited to telomeres. Consistent with the observations from cellular experiments, the tumorigenic potential of cancer cells was also reduced in mouse xenografts after BMVC treatments. Thus, BMVC repressed tumor progression through both telomere-dependent and telomere-independent pathways. (Mol Cancer Res 2008;6(6):955–64)
A Novel Unidirectional Cross-Talk from the Insulin-Like Growth Factor-I Receptor to Leptin Receptor in Human Breast Cancer Cells
Authors: Ozbay Tuba , Nahta Rita
Published: May 2008

Obesity is a major risk factor for the development and progression of breast cancer. Increased circulating levels of the obesity-associated hormones leptin and insulin-like growth factor-I (IGF-I) and overexpression of the leptin receptor (Ob-R) and IGF-I receptor (IGF-IR) have been detected in a majority of breast cancer cases and during obesity. Due to correlations between increased leptin, Ob-R, IGF-I, and IGF-IR in breast cancer, we hypothesized that molecular interactions may exist between these two signaling pathways. Coimmunoprecipitation and immunoblotting showed that IGF-IR and Ob-R interact in the breast cancer cell lines MDA-MB-231, MCF7, BT474, and SKBR3. Stimulation of cells with IGF-I promoted Ob-R phosphorylation, which was blocked by IGF-IR kinase inhibition. In addition, IGF-I activated downstream signaling molecules in the leptin receptor and IGF-IR pathways. In contrast to IGF-I, leptin did not induce phosphorylation of IGF-IR, indicating that receptor cross-signaling is unidirectional, occurring from IGF-IR to Ob-R. Our results show, for the first time, a novel interaction and cross-talk between the IGF-I and leptin receptors in human breast cancer cells. (Mol Cancer Res 2008;6(6):1052–8)
Inhibitory Effects of Eicosapentaenoic Acid on Chronic Cerebral Vasospasm after Subarachnoid Hemorrhage: Possible Involvement of a Sphingosylphosphorylcholine-Rho-Kinase Pathway
Authors: Shirao Satoshi , Fujisawa Hirosuke , Kudo Akira , Kurokawa Tetsu , Yoneda Hiroshi , Kunitsugu Ichiro , Ogasawara Kuniaki , Soma Masaaki , Kobayashi Sei , Ogawa Akira , Suzuki Michiyasu
Published: June 2008

Background and Purpose: Rho-kinase (ROK)-mediated Ca2+ sensitization of vascular smooth muscle (VSM) contraction plays a pivotal role in cerebral vasospasm (CV). We previously demonstrated that sphingosylphosphorylcholine (SPC) induces Ca2+ sensitization through sequential activation of the Src family protein tyrosine kinases (Src-PTKs) and ROK in vitro, and that Ca2+ sensitization is inhibited by eicosapentaenoic acid (EPA) through the selective inactivation of Src-PTK. In this study, we examined whether SPC induced CV in vivo, and, if it did, whether EPA would inhibit CV, as induced by SPC or in an in vivo model of subarachnoid hemorrhage (SAH). Methods: Changes in the diameter of the canine basilar artery were investigated by angiography after administering SPC into the cisterna magna. Then, Y27632, a specific Rho-kinase inhibitor, or EPA was injected intracisternally and the effects of both agents were investigated. In another experiment using a single-hemorrhage model, Y27632 or EPA was injected on day 7 after SAH and the changes in the diameter of the canine basilar artery were investigated. Results: At cerebrospinal fluid concentrations of 100 and 300 µmol/l, SPC induced severe vasoconstriction (maximum vasoconstriction by SPC (100 µmol/l): 61.8 ± 8.2%), which was markedly reversed by Y27632 (96.3 ± 4.4%) or EPA (92.6 ± 12.8%). SAH caused severe vasospasm on day 7 (67.6 ± 7.8%), which was significantly blocked by Y27632 (95.5 ± 10.6%) or EPA (90.0 ± 4.4%). Conclusions: SPC is a novel mediator of ROK-induced CV in vivo. The inhibition of CV induced by SPC or after SAH by EPA suggests beneficial roles of EPA in the treatment of CV. Our findings are compatible with the notion that the SPC-ROK pathway may be involved in CV.
Fever Accentuates Transmural Dispersion of Repolarization and Facilitates Development of Early Afterdepolarizations and Torsade de Pointes Under Long-QT Conditions
Authors: Burashnikov Alexander , Shimizu Wataru , Antzelevitch Charles
Published: May 2008

Background—

The arrhythmogenic effects of hyperthermia have been highlighted in the Brugada syndrome but remain largely unexplored in other arrhythmic syndromes. The present study examines the effect of hyperthermia on transmural dispersion of action potential duration (TD-APD), early afterdepolarization (EAD) activity, and torsade de pointes (TdP) under long-QT conditions.

Methods and Results—

Standard and floating glass microelectrodes were used to record action potentials from epicardial, M cell, and endocardial regions of the arterially perfused left ventricle wedge, from tissue slices isolated from these regions, and from isolated Purkinje fibers. A transmural ECG was simultaneously recorded across the wedge. Under baseline conditions and in the presence of I
Ks
block (chromanol 293B), hyperthermia (39�C to 40�C) abbreviated APD in tissue slices from all 3 regions. In the presence of I
Kr
block (E-4031), hyperthermia prolonged APD and induced or augmented EADs in M cell and Purkinje preparations at pacing cycle lengths ≥800 ms but abbreviated APD in epicardium and endocardium, resulting in a marked accentuation of TD-APD. Ryanodine prevented the hyperthermia-induced EAD. In perfused wedge preparations, hyperthermia abbreviated APD throughout both in the absence or presence of I
Kr
or I
Ks
block and did not induce EADs or TdP. Combined I
Kr
and I
Ks
block increased TD-APD and induced EADs (4/12) and spontaneous TdP (3/12) at 36�C to 37�C; hyperthermia (39�C to 40�C) further accentuated TD-APD and facilitated the development of EAD activity (9/12) and TdP (6/12).

Conclusions—

Our findings suggest that hyperthermia can be associated with an increased arrhythmic risk when the repolarization reserve of the myocardium is compromised.
Functional Effects of
KCNE3
Mutation and Its Role in the Development of Brugada Syndrome
Authors: Delpón Eva , Cordeiro Jonathan M. , Núñez Lucía , Thomsen Poul Erik Bloch , Guerchicoff Alejandra , Pollevick Guido D. , Wu Yuesheng , Kanters J�rgen K. , Larsen Carsten Toftager , Hofman-Bang Jacob , Burashnikov Elena , Christiansen Michael , Antzelevitch Charles
Published: May 2008

Background—

The Brugada syndrome, an inherited syndrome associated with a high incidence of sudden cardiac arrest, has been linked to mutations in 4 different genes, leading to a loss of function in sodium and calcium channel activity. Although the transient outward current (
I
to
) is thought to play a prominent role in the expression of the syndrome, mutations in
I
to
-related genes have not been identified as yet.

Methods and Results—

One hundred five probands with the Brugada syndrome were screened for ion channel gene mutations using single-strand conformation polymorphism electrophoresis and direct sequencing. A missense mutation (R99H) in
KCNE3
(
MiRP2
) was detected in 1 proband. The R99H mutation was found 4/4 phenotype-positive and 0/3 phenotype-negative family members. Chinese hamster ovary-K1 cells were cotransfected using wild-type (WT) or mutant
KCNE3
and either WT KCND3 or KCNQ1. Whole-cell patch clamp studies were performed after 48 hours. Interactions between Kv4.3 and
KCNE3
were analyzed in coimmunoprecipitation experiments in human atrial samples. Cotransfection of R99H-
KCNE3
with
KCNQ1
produced no alteration in tail current magnitude or kinetics. However, cotransfection of R99H
KCNE3
with
KCND3
resulted in a significant increase in the
I
to
intensity compared with WT
KCNE3
+KCND3. Using tissues isolated from the left atrial appendages of human hearts, we also demonstrate that
K
v
4.3
and
KCNE3
can be coimmunoprecipitated.

Conclusions—

These results provide definitive evidence for a functional role of
KCNE3
in the modulation of
I
to
in the human heart and suggest that mutations in
KCNE3
can underlie the development of the Brugada syndrome.
A Novel Human-Specific Soluble Vascular Endothelial Growth Factor Receptor 1
Authors: Sela Shay , Itin Ahuva , Natanson-Yaron Shira , Greenfield Caryn , Goldman-Wohl Debra , Yagel Simcha , Keshet Eli
Published: May 2008

A human-specific splicing variant of vascular endothelial growth factor (VEGF) receptor 1 (Flt1) was discovered, producing a soluble receptor (designated sFlt1-14) that is qualitatively different from the previously described soluble receptor (sFlt1) and functioning as a potent VEGF inhibitor. sFlt1-14 is generated in a cell type-specific fashion, primarily in nonendothelial cells. Notably, in vascular smooth muscle cells, all Flt1 messenger RNA is converted to sFlt1-14, whereas endothelial cells of the same human vessel express sFlt1. sFlt1-14 expression by vascular smooth muscle cells is dynamically regulated as evidenced by its upregulation on coculture with endothelial cells or by direct exposure to VEGF. Increased production of soluble VEGF receptors during pregnancy is entirely attributable to induced expression of placental sFlt1-14 starting by the end of the first trimester. Expression is dramatically elevated in the placenta of women with preeclampsia, specifically induced in abnormal clusters of degenerative syncytiotrophoblasts known as syncytial knots, where it may undergo further messenger RNA editing. sFlt1-14 is the predominant VEGF-inhibiting protein produced by the preeclamptic placenta, accumulates in the circulation, and hence is capable of neutralizing VEGF in distant organs affected in preeclampsia. Together, these findings revealed a new natural VEGF inhibitor that has evolved in humans, possibly to protect nonendothelial cells from adverse VEGF signaling. Furthermore, the study uncovered the identity of a VEGF-blocking protein implicated in preeclampsia.
Aryl Hydrocarbon Receptor Is Activated by Glucose and Regulates the Thrombospondin-1 Gene Promoter in Endothelial Cells
Authors: Dabir Pankaj , Marinic Tina E. , Krukovets Irene , Stenina Olga I.
Published: May 2008

Hyperglycemia is an independent risk factor for development of diabetic vascular complications. The molecular mechanisms that are activated by glucose in vascular cells and could explain the development of vascular complications are still poorly understood. A putative binding site for the transcription factor aryl hydrocarbon receptor (AhR) was identified in the glucose-responsive fragment of the promoter of thrombospondin-1, a potent antiangiogenic and proatherogenic protein involved in development of diabetic vascular complications. AhR was expressed in aortic endothelial cells (ECs), activated, and bound to the promoter in response to high glucose stimulation of ECs. The constitutively active form of AhR induced activation of the thrombospondin-1 gene promoter. In response to high glucose stimulation, AhR was found in complex with Egr-1 and activator protein-2, which are 2 other nuclear transcription factors activated by glucose in ECs that have not been previously detected in complex with AhR. The activity of the DNA-binding complex was regulated by glucose through the activation of hexosamine pathway and intracellular glycosylation. This is the first report of activation of AhR (a receptor for xenobiotic compounds) by a physiological stimulus. This report links the activation of AhR to the pathological effects of hyperglycemia in the vasculature.
Influence of Aging and Menopause on Lipids and Lipoproteins in Women
Authors: Kolovou Genovefa D. , Bilianou Helen G.
Published: May 2008

The actions of endogenous estrogens on the cardiovascular system can be mediated directly on the vessels or indirectly through the modulation of cardiovascular risk factors. Aging and menopause are the main causes that lead to an adverse lipid profile in women. The influence of age on prevalence of increased plasma triglyceride levels and on larger variation in fasting triglyceride levels has been reported in both genders. However, the increased prevalence of increased cholesterol with age was only found in women. The high-density lipid cholesterol level is higher in women than in men throughout all ages. Obesity may also exaggerate the unfavorable lipid profile in aging and/or menopausal women. In the last decades the management of the menopausal women has been a subject of concern for medical scientific groups. In this review, the current understanding of an influence of age and menopause on lipids and lipoproteins concentration in women will be analyzed.
International Business Dynamics
Authors: Bartkus Viva Ona , Davis James H.
Published: May 2008

Globalization of the world economy and proliferation of multinational corporations (MNCs) has dramatically affected the power balance among international actors. On one hand, MNCs have long influenced the states in which they operate, with the consequent erosion of state sovereignty. On the other, states directly affect MNCs, in effect becoming another factor of production in addition to the economist’s traditional set of labor, land, and capital. This article introduces a theoretical model based on the interaction of the MNC, the local state, and the local market to predict and explain the economic returns that the MNC will earn on its investment in the local market.
Escape From Los Angeles
Authors: Schneider Jack
Published: May 2008

In 1960, Los Angeles was still a decidedly white city. By 1980, it no longer was. What happened in Los Angeles was not uncommon elsewhere, as white residents fled city centers in the latter half of the twentieth century to pursue visions of the suburban good life. Whites abandoned central cities, and as a consequence, the school systems of those urban areas began to reflect their populations—struggling, under-resourced, and non-white. But in Los Angeles, this phenomenon seems to have happened in reverse. Whites with school-age children fled the public school system at even greater rates than those at which they left the city, and at much greater rates than other white residents. Driving families out of Los Angeles public schools was the specter of school desegregation, which threatened to bring populations associated with violence and low academic performance into neighborhood schools. The threat desegregation posed to public schools caused parents to choose private schools, if they could, and reevaluate the quality of life in Los Angeles, if needed. Their subsequent out-migration brought about the schools they feared and forever changed the face of the city they left.
The Struggle Over Redevelopment At Cabrini-Green, 1989-2004
Authors: Miller Brian J.
Published: May 2008

Over the past three decades, American public housing authorities have advocated the demolition of high-rise public housing projects. Since the late 1980s, governments and local groups have developed plans to tear down the Cabrini-Green public housing project located in the Near North neighborhood in Chicago. The plans call for the demolition of the Cabrini high-rises and replacing them with mixed-income neighborhoods. The new communities are intended to help the public housing residents by reducing their social and economic isolation. Some of the Cabrini residents have fought the redevelopment plans in court because they argue that the new communities are not adequate for the number of displaced residents. Due to court injunctions, the redevelopment has been a slow process: while some of the high-rises have been torn down and several mixed-income developments have been built near Cabrini, a number of high-rises remain. Questions surrounding the resistance at Cabrini-Green and implications for the future of public housing policy are briefly considered
Drug Use in Sport
Authors: Stewart Bob , Smith Aaron C.T.
Published: May 2008

Many of the models and theories that aim to explain drug use in sport are limited by a focus on individual athlete decision-making that centers on the socioeconomic costs and benefits of using drugs. However, this limitation narrows the debate to how various penalties and sanctions might curb use. The authors suggest that to broaden the debate the investigation should include an exploration of the context in which drug use occurs and a situational diagnosis of the assumptions, values, and beliefs that underpin drug use in sport. To this end, the authors have developed a model of drug use in sport that combines the micro orientation of individual athlete and interpersonal behavior with the macro orientation of sporting context, structure, and culture. They use this contextualized model to contrast a use-reduction policy with a harm-minimization policy that allows sport organizations and athletes to manage their drug use in a safe and secure environment.
Measuring Breast Cancer and Mammography Screening Beliefs Among Chinese American Immigrants
Authors: Lee-Lin Frances , Menon Usha , Pett Marjorie , Nail Lillian , Lee Sharon , Mooney Kathi
Published: May 2008

Disparities in breast cancer outcomes persist among Asian American women. Breast cancer is the most commonly diagnosed cancer among Chinese American women. This article describes the psychometric evaluation of an instrument measuring knowledge and beliefs related to breast cancer and screening among Chinese American women aged 40 or older. A sample of 100 foreign-born Chinese American women were recruited from an Asian community. Guided by the health belief model, a questionnaire was adapted from three existing questionnaires. Principal axis factoring analyses yielded a three-factor solution that accounted for 53% of the variance in the breast cancer items and a four-factor solution that accounted for 69% of the variance in the cultural items (Cronbach's alphas = .71—.89). Whereas these findings contribute to the understanding of the psychometric properties of an instrument targeted for Chinese American women, additional research is needed to evaluate its utility and efficacy for other Asian Americans.
The Impact of Personalized Prenotification on Response Rates to an Electronic Survey
Authors: Hart Ann Marie , Brennan Caitlin W. , Sym Donna , Larson Elaine
Published: May 2008

The purpose of this post-hoc investigation was to determine the difference in response rates between respondents who received personalized prenotification prior to receiving an electronic survey and those who did not. An electronic survey was e-mailed to 236 program directors or other designated individuals from nurse practitioner (NP) programs around the United States. Seventy six percent of the NP program directors were personally contacted about the survey in advance, and 97.5% agreed to participate. The remaining 24% were sent e-mails with a link to the survey without prenotification. Response rates for those in the prenotification group who had agreed to participate versus those who did not receive prenotification were 49% and 45%, respectively. Personalized prenotification did not affect the electronic survey response rates. Electronic research methodology offers a unique opportunity to potentially survey an entire population (e.g., nursing faculty), thus further investigation regarding factors associated with electronic survey response rates and ways to improve these rates is warranted.
Adolescents' Avoidance of Secondhand Smoke Exposure
Authors: Wang Wen-Ling , Herting Jerald R. , Tung Yuk-Ying
Published: May 2008

More than half of young adolescents, 13 to 15 years old, suffer exposure to secondhand smoke (SHS) at home and in public places. Despite threats to adolescent health and well-being, little research has been done to identify factors that enable adolescents to avoid SHS. The objective of this study was to develop a model to predict SHS avoidance behavior among young adolescents. The impact of gender differences on predictor variances was investigated. Model testing was conducted using structural equation modeling on data from 1,291 nonsmoking Taiwanese middle school students. Attitude toward SHS is an important factor influencing the avoidance behavior of adolescents. The explanatory model of SHS avoidance behaviors provides useful information for program development aimed at decreasing adolescent exposure to SHS. Interventions focused on influencing adolescent attitudes toward SHS and supporting avoidance self-efficacy are needed.
Ethical questions in human clinical psychopharmacology: should the focus be on placebo administration?
Authors: Kotzalidis GD , Pacchiarotti I. , Manfredi G. , Savoja V. , Torrent C. , Mazzarini L. , Tatarelli C. , Amann B. , Di Marzo S. , Sánchez-Moreno J. , Sani G. , Girardi P. , Colom F. , Vieta E.
Published: May 2008

Of all ethical issues in clinical trial designs, only placebo use is dealt with acrimony and unwarranted, rhetoric emphasis. Many misconceptions are biased and may hamper research in the mechanisms of healing and recovery if placebo is banned from clinical trials, as some influential ethicists propose. Current treatments in psychiatry are by no means optimal and may vary in their effect across studies, rendering difficult to find the best available therapeutic method with which to compare new drugs. Because drugs possess specific mechanisms, it is not possible to compare drugs with different mechanisms as to their relevance in the pathophysiology of a given disorder. Placebo acts through non-specific mechanisms and is the ideal control for any disorder whose pathophysiology is relatively unknown and its treatment is still suboptimal. Sticking to short-term patient benefit in a trial reflects an individualistically oriented thinking in contemporary ethics and is likely to limit further research and efforts to better understand the mechanisms of disease and drug action, but also those related to general body reactance and self-healing, which are enhanced by placebo administration. Because in history ethics are swinging between two opposed views, it is possible that in the near future, the balance will move towards communitarianism, which is more likely to better serve long-term patient needs. Ethicists should also consider some other aspects of human experimentation, such as the consistency of research lines and the trend to substitute older drugs with their metabolites or enantiomers.
Memory impairments in humans after acute tryptophan depletion using a novel gelatin-based protein drink
Authors: Sambeth A. , Riedel WJ , Tillie DE , Blokland A. , Postma A. , Schmitt JAJ
Published: May 2008

Acute tryptophan depletion (ATD) can be used to decrease serotonin levels in the brain. Traditionally, ATD has been established by administering amino acid (AA) mixtures and studies using this method showed that serotonin is involved in learning and memory processes. This study used a recently developed gelatin-based protein drink to examine whether it 1) is superior to the traditional AA method in controlling the tryptophan levels in the placebo condition, 2) impairs long-term memory and 3) differentially affects episodic and spatial memory. Sixteen healthy subjects participated in a double-blind, placebo-controlled study. Memory was assessed using a visual verbal learning test and an object relocation task (spatial memory). Tryptophan ratio significantly decreased after ATD and did not significantly increase in the placebo condition. Delayed recall in the verbal learning test and delayed relocation of objects to positions in the spatial task were impaired after ATD. Spatial short-term memory, however, improved. The current results indicate that the tryptophan levels were essentially neutral in the placebo condition compared with those in the traditional AA mixture. Our study provides further evidence that impairment in long-term episodic and elementary spatial memory after ATD is related to lowered tryptophan levels in plasma.
Effects of atomoxetine on subjective and neurocognitive symptoms of nicotine abstinence
Authors: Ray R , Rukstalis M , Jepson C , Strasser AA , Patterson F , Lynch K , Lerman C
Published: May 2008

Abstract

Nicotine dependence has been linked to attention-deficit hyperactivity disorder (ADHD) symptoms in both clinical and general populations. This behavioural pharmacology study used a within-subject, double-blind, crossover design to test the effects of atomoxetine, a medication for ADHD, on nicotine abstinence symptoms. Fifty non treatment–seeking smokers (≥15 cigarettes/day) completed a baseline session when they were smoking as usual and then two laboratory testing sessions after overnight abstinence and treatment with 7 days of either atomoxetine (1.2 mg/kg) or placebo. During each laboratory session, participants completed subjective measures of abstinence symptoms and performed neurocognitive tasks. In mixed effects models, atomoxetine, compared with placebo, was found to be associated with a reduction in abstinence-induced subjective withdrawal symptoms. Atomoxetine was also associated with significant reductions in self-reported smoking urges amongst smokers who scored high on a baseline measure of smoking for stimulation. However, atomoxetine had no effect on any of the cognitive tasks employed in the study. Thus, atomoxetine may reduce cravings to smoke among smokers who use nicotine to increase arousal.
Effect of intrapulmonary tetrahydrocannabinol administration in humans
Authors: Zuurman L. , Roy C. , Schoemaker RC , Hazekamp A. , den Hartigh J. , Bender JCME , Verpoorte R. , Pinquier JL , Cohen AF , van Gerven JMA
Published: May 2008

This randomised, double-blind, placebo-controlled, cross-over study was designed to identify which pharmacodynamic parameters most accurately quantify the effects of delta-9-Tetrahydrocannabinol (THC), the predominantly psychoactive component of cannabis. In addition, we investigated the acceptability and usefulness of a novel mode of intrapulmonary THC administration using a Volcano® vaporizer and pure THC instead of cannabis. Rising doses of THC (2, 4, 6 and 8 mg) or vehicle were administered with 90 minutes intervals to twelve healthy males using a Volcano® vaporizer. Very low between-subject variability was observed in THC plasma concentrations, characterising the Volcano® vaporizer as a suitable method for the administration of THC. Heart rate showed a sharp increase and rapid decline after each THC administration (8 mg: 19.4 bpm: 95% CI 13.2, 25.5). By contrast, dose dependent effects of body sway (8 mg: 108.5%: 95% CI 72.2%, 152.4%) and different subjective parameters did not return to baseline between doses (Visual Analogue Scales of 'alertness' (8 mg: -33.6 mm: 95% CI -41.6, -25.7), 'feeling high' (8 mg: 1.09 U: 95% CI 0.85, 1.33), 'external perception' (8 mg: 0.62 U: 95% CI 0.37, 0.86)). PK/PD-modeling of heart rate displayed a relatively short equilibration half-life of 7.68 min. CNS parameters showed equilibration half-lives ranging between 39.4 - 84.2 min. Some EEG-frequency bands, and pupil size showed small changes following the highest dose of THC. No changes were seen in saccadic eye movements, smooth pursuit and adaptive tracking performance. These results may be applicable in the development of novel cannabinoid agonists and antagonists, and in studies of the pharmacology and physiology of cannabinoid systems in humans.
Obsessive-compulsive disorder in UK clozapine-treated schizophrenia and schizoaffective disorder: a cause for clinical concern
Authors: Mukhopadhaya K. , Krishnaiah R. , Taye T. , Nigam A. , Bailey AJ , Sivakumaran T. , Fineberg NA
Published: May 2008

The association between schizophrenia and obsessive-compulsive disorder (OCD) is complex. This study systematically examined a UK cohort of clozapine-treated individuals with schizophrenia/schizoaffective disorder. Fourteen of 59 cases (24%) scored positively on item H of the Mini-International Neuropsychiatric Interview (MINI) for OCD. The mean Yale— Brown Obsessive-Compulsive Scale (Y-BOCS) score in MINI-positive cases was 17.6 (SD ± 6.3). Sixty-four percent scored 16 or more on the Y-BOCS, representing clinically meaningful illness severity. Seven (50%) patients with OCD had previously received the diagnosis by their treating clinicians and were already receiving with selective serotonin re-uptake inhibitors (SSRIs) treatment. OCD cases scored significantly worse than their non-OCD counterparts on the Abnormal Involuntary Movement Scale (P = 0.01) and the Simpson Angus Scale (SAS; P = 0.01). There was also a non-significant trend toward higher ratings for OCD cases on the Clinical Global Impression-Schizophrenia scale (P = 0.06). Comparing the OCD cases taking SSRI (n = 7) with those not on SSRI (n = 7), significant differences emerged on the SAS (P = 0.03). Our results suggest that OCD is common among patients receiving clozapine for schizophrenic disorders and that the comorbidity is associated with greater motoric impairment. The role of medication in this condition remains unclear.
Lithium carbonate in the management of cannabis withdrawal in humans: an open-label study
Authors: Winstock AR , Lea T. , Copeland J.
Published: May 2008

Cannabis is the most widely used illicit substance in the world. Estimates suggest that approximately 10—20% of cannabis users meet criteria for cannabis dependence and a significant proportion experience withdrawal discomfort on cessation of use. To date, there has been an absence of any clinically validated treatments to manage withdrawal. The current study is an open-label trial exploring the utility of lithium carbonate for the management of cannabis withdrawal symptoms in treatment seeking adult humans. In total, 20 participants were recruited to the study (19 men). All met DSM-IV cannabis-dependence criteria and had been smoking cannabis daily or almost daily for a mean 9 years. Participants were admitted to an inpatient detoxification facility and prescribed lithium 500 mg b.d. for 7 days. Cannabis withdrawal was assessed daily with the Marijuana Withdrawal Checklist (MWC). Two participants were withdrawn from the trial because of possible adverse effects. Sixty percent of participants completed the 7-day treatment program. Follow-up was conducted at a mean of 107 days following treatment. The mean percentage of days abstinent in the period between treatment cessation and follow-up was 87.57%. Twenty-nine percent of participants (n = 5) reported continuous abstinence that was biochemically verified at follow-up. Agreement between self-reported cannabis use and urinalysis at follow-up was moderate (κ = 0.47). Significant reductions in symptoms of depression and anxiety and cannabis-related problems were also reported. This study provides evidence for the potential clinical utility and safety of lithium in the management of cannabis withdrawal. A randomised, placebo-controlled trial is recommended.
Effects of bifeprunox and aripiprazole on rat serotonin and dopamine neuronal activity and anxiolytic behaviour
Authors: Dahan L , Husum H , Mnie-Filali O , Arnt J , Hertel P , Haddjeri N
Published: May 2008

Abstract

The atypical antipsychotic bifeprunox is a partial dopamine D2and 5-HT1Areceptor agonist. Using in-vivo electrophysiological and behavioural paradigms in the rat, the effects of bifeprunox and aripiprazole were assessed on ventral tegmental area (VTA) dopamine and dorsal raphe serotonin (5-HT) cell activity and on foot shock–induced ultrasonic vocalisation (USV). In VTA, bifeprunox and aripiprazole decreased (by 20–50%) firing of dopamine neurons. Interestingly, bursting activity was markedly reduced (by 70–100%), bursting being associated with a larger synaptic dopamine release than single spike firing. Both ligands reduced inhibition of firing rate induced by the full dopamine receptor agonist apomorphine, whereas the D2receptor antagonist haloperidol prevented these inhibitory effects, confirming partial D2-like agonistic properties. On 5-HT neurons, bifeprunox was more potent than aripiprazole to suppress firing activity. The 5-HT1Areceptor antagonist WAY-100,635 prevented their effects. In the USV test of anxiolytic-like activity, bifeprunox had higher potency than aripiprazole to reduce vocalisations. Both WAY-100,635 and haloperidol reversed the effects of both agonists. The present in-vivo study shows that bifeprunox is a potent partial D2-like and 5-HT1Areceptor agonist reducing preferentially the phasic activity of dopamine neurons. Thus, bifeprunox would be expected to be an effective compound against positive and negative symptoms of schizophrenia.
The influences of depression and venlafaxine use at therapeutic doses on atrial conduction
Authors: Emul M , Dalkiran M , Samim S , Yıldırım E , Bayar R , Balcioglu I , Keles I
Published: May 2008

Abstract

Patients with depression have increases risk of cardiac mortality. Overdose with venlafaxine has been accused of supraventricular tachycardia, atrial fibrillation and other cardiac effects. Discontinuous and inhomogeneous propagation of sinus impulses in atrium plays a major role in atrial fibrillation. We aimed to measure the effects of venlafaxine therapy on propagation of sinus impulses reflections in electrocardiography in depression. Eligible 19 participants were outpatients with depression. 75 mg/day dose of venlafaxine was administered to the patients. The patients were asked to complete both Beck Depression and Anxiety Inventories. 17 healthy participants enrolled in the study. The electrocardiography records were obtained while patients were drug naive and one week after treatment. The baseline durations of Pminimumand Pmaximumin the patient group were significantly shorter than controls (p < 0,05). The differences between baseline and after venlafaxine therapy among electrocardiographical variables were statistically insignificant. There were no significant correlations between age, sex, body mass index, clinical inventories and electrocardiographical variables in both patients and controls. Autonomic dysregulation in myocardium is still inconclusive in depression. Venlafaxine at therapeutic dose of 75 mg/day does not seem to be associated with myocardial conduction dysregulation.
A case of aripiprazole and tardive dyskinesia
Authors: Abbasian C , Power P
Published: May 2008

Abstract

This is a case report of a 24-year-old African lady, who developed symptoms of tardive dyskinesia (TD) following 9 months of treatment with aripiprazole 15 mg. She has no family history of mental illness, not used illicit substances and has a medical diagnosis of idiopathic hypertension which is well controlled. The patient has an 18-month history of paranoid schizophrenia with three psychotic episodes, one severe enough to warrant admission. Upon discontinuation of aripiprazole and switch to quetiapine, the symptoms of TD disappeared rapidly. A PubMed search revealed one previous case report of aripiprazole and TD. The authors recommend maintaining vigilance regarding all possible side-effects irrespective of the type of antipsychotic being used.
Is valproate promising in cardiac fatal arrhythmias? Comparison of P- and Q-wave dispersion in bipolar affective patients on valproate or lithium–valproate maintenance therapy with healthy controls
Authors: E Kurt , M Emul , O Ozbulut , O Guler , F Erdur , H Sağlam , O Gecici
Published: May 2008

Abstract

Autonomic nerve system is considered to be involved in bipolar affective disorder (BAD) or to be influenced by valproate monotherapy or valproate plus lithium combination. We planned to assess the effects of medication on atrial and ventricular conduction. The electrocardiography records were performed with eligible 15 patients with valproate, 20 patients with lithium–valproate combination use in euthymic phases of BAD and 20 healthy participants. The blood valproate and lithium concentrations in groups were in normal range. The difference in P maximum, P minimum, maximum QTc were statistically insignificant. Minimum QTc ( F = 6.36; df = 2; P = 0.003) and QT dispersion (QTD) ( F = 5.57; df = 2; P = 0.006) were statistically significant among the groups. There were no significant differences between patient groups among ECG parameters. Minimum QTc was significantly longer in combination group than healthy controls, whereas the QTD values in both patient groups were significantly lower than controls’. Valproate might have some preventive effects on ventricular electrical conduction because of lower QTD in both patient groups. Thus, valproate seems to have cardiac conduction stabilizing effect beside its mood stabilizing aspect. However, this finding needs replication and further corroboration in well-designed studies.
Aripiprazole in the treatment of patients with alcohol dependence: a double-blind, comparison trial vs. Naltrexone
Authors: Martinotti G , Di Nicola M , Di Giannantonio M , Janiri L
Published: May 2008

Abstract

Substantial evidence suggests that both partial dopamine agents and mixed 5-HT1A/2A receptor drugs independently show significant efficacy in reducing alcohol use in both animals and humans. Aripiprazole, which acts as a dopamine/5-HT system stabilizer, approaches the optimal characteristics sought in medication to be considered for testing in the treatment of alcohol dependence. In this randomised, double-blind, confrontation trial with naltrexone, we aimed to investigate the efficacy of aripiprazole on alcohol-drinking indices. Craving and psychiatric symptom improvements were the secondary end points. Seventy-five alcohol dependent subjects were detoxified and were subsequently randomised into two groups, receiving 50 mg of naltrexone and 5–15 mg of aripiprazole, respectively. Craving (Visual Analogue Scale; Obsessive and Compulsive Drinking Scale) and withdrawal (Clinical Institute Withdrawal Assessment) rating scales were applied; psychiatric symptoms were evaluated through the Symptom Check List 90–Revised. The number of subjects remained alcohol free for the entire study period (16 weeks) and the number of subjects relapsed were not significantly different in the two groups. The survival function showed that patients treated with aripiprazole remained abstinent from any alcohol amount for a longer time with respect to those treated with naltrexone. As for craving scores, patients treated with naltrexone showed a better outcome. Results from this study globally place aripiprazole at the same range of efficacy of naltrexone, one of the approved drugs used in alcohol relapse prevention. If it could be demonstrated in placebo-controlled trials that aripiprazole is efficacious in decreasing alcohol use, lessening craving, and attenuating psychopathological symptom severity, we will have gained a powerful agent for the treatment of alcohol-dependent subjects.
Effects of acute alcohol consumption on processing of perceptual cues of emotional expression
Authors: Attwood AS , Ohlson C. , Benton CP , Penton-Voak IS , Munafò MR
Published: May 2008

Alcohol consumption has been associated with increases in aggressive behaviour. However, experimental evidence of a direct association is equivocal, and mechanisms that may underlie this relationship are poorly understood. One mechanism by which alcohol consumption may increase aggressive behaviour is via alterations in processing of emotional facial cues. We investigated the effects of acute alcohol consumption on sensitivity to facial expressions of emotion. Participants attended three experimental sessions where they consumed an alcoholic drink (0.0, 0.2 or 0.4 g/kg), and completed a psychophysical task to distinguish expressive from neutral faces. The level of emotion in the expressive face varied across trials the threshold at which the expressive face was reliably identified and measured. We observed a significant three-way interaction involving emotion, participant sex and alcohol dose. Male participants showed significantly higher perceptual thresholds for sad facial expressions compared with female participants following consumption of the highest dose of alcohol. Our data indicate sex differences in the processing of facial cues of emotional expression following alcohol consumption. There was no evidence that alcohol altered the processing of angry facial expressions. Future studies should examine effects of alcohol expectancy and investigate the effects of alcohol on the miscategorisation of emotional expressions.
Modelling the anxiety-depression continuum in chicks
Authors: Warnick JE , Huang CJ , Acevedo EO , Sufka KJ
Published: May 2008

Abstract

The clinical syndromes of anxiety and depression are now thought to exist along a temporal continuum and this construct has been modelled in a preclinical setting in chicks separated from conspecifics. This research sought to further the validity of the chick anxiety-depression continuum model. Dose–response studies using two classes of anxiolytics (chlordiazepoxide: 2.5, 5.0, 10.0, 15.0 mg/kg, and clonidine: 0.1, 0.15, 0.2, 0.25 mg/kg) and three classes of antidepressants (imipramine: 1.0, 3.0, 10.0, 15.0 mg/kg, maprotoline: 2.5, 5.0, 10.0, 20.0 mg/kg and fluoxetine: 1.0, 5.0, 10.0, 20.0 mg/kg) showed an ability to detect anxiolytic activity of chlordiazepoxide, clonidine, imipramine and maprotoline in the anxiety-like phase of the model and to detect antidepressant effects of imipramine, maprotoline and fluoxetine in the depression-like phase of the model. In addition, blood plasma interleukin-6, a biomarker of stress, was found to be elevated in response to social-separation stress. Collectively, these findings further characterize the model as a simulation of the anxiety-depression continuum and begin to establish the paradigm as a high-utility adjuvant to rodent screening assays for putative anxiolytic and antidepressant compounds.
Antidepressant-associated mania: soon after switch from fluoxetine to mirtazapine in an elderly woman with mixed depressive features
Authors: Liu CC , Liang KY , Liao SC
Published: May 2008

Abstract

Mirtazapine augmentation to a serotonin-reuptake inhibitor has been proposed to boost antidepressant effects and more likely to induce manic switch. Such a combined antidepressant therapy strategy should be used carefully if the patient’s refractoriness is attributable to mixed depressive features. Mixed depression is more difficult to be treated by antidepressant monotherapy and related to higher risk of manic switch during treatment. We report a case with no previous history of bipolar disorder, whereas developed full-blown psychotic manic symptoms soon after switch from fluoxetine to mirtazapine. The patient’s premorbid characters and clinical presentations suggested an implicit bipolarity that predisposed her to a manic switch. Her manic switch was likely to be triggered by a simulated combined effect because of complex drug interactions during shifting from fluoxetine to mirtazapine. For patients in mixed depressive states, mood stabilizers are preferable to antidepressants.
Recurrent relapses of depression in a patient established on sertraline after taking herbal medicinal mixtures – a herb–drug interaction?
Authors: Prasad KPRC , Tharangani PGD , Samaranayake CN
Published: May 2008

Abstract

We describe a patient with depression who was well controlled with sertraline monotherapy developing two relapses of depression in close temporal relationship with starting ayurvedic herbal mixtures. We discuss the possibility of a pharmacokinetic herb–drug interaction decreasing the therapeutic efficacy of sertraline leading to the relapses of depression. We speculate the herbal plant most likely to be responsible for this interaction is either Terminalia chebula or Commiphora wighteii.
Safety of therapeutic methylphenidate in adults: a systematic review of the evidence
Authors: Godfrey J
Published: May 2008

Abstract

Attention deficit hyperactivity disorder (ADHD) often persists into adulthood. Stimulant drugs, including methylphenidate, have showed efficacy in trials for ADHD in adults. Adult psychiatrists are likely to encounter increasing numbers of adult patients who may benefit from methylphenidate. A systematic review of the literature was made to examine the evidence on the safety of methylphenidate, when used therapeutically in adults. Twenty-six placebo-controlled trials were found, in which 811 adults received methylphenidate for ADHD and other conditions. In the short term, methylphenidate was well tolerated and no serious side effects were observed. There is little information on the long-term safety of methylphenidate in adults, although the number of serious adverse effects reported to regulatory authorities has, so far, been low. Methylphenidate is associated with a modest rise in blood pressure and heart rate. Surveys of stimulant use in US universities show that misuse of prescribed medication, for recreation or to enhance study, is fairly common although the level of harm that arises from this practice is unclear.