bluuebunny/crossref_metadata_2025 huggingface dataset:
Home care for older people
Authors: Toiviainen Leila
Published: February 2006

Older people receive home care either by choice or because alternative means of care are not available. The reasons for home care have an economic and cultural component; most of it is provided on a voluntary basis, regardless of the culture of the older person. Good home care, however, should not be left entirely to volunteers, but should be supported by the state through legislation and social policies, especially in the area of primary care and health promotion, as should end-of-life care. By these means some of the negative effects of home care on the recipient and the carer can be reduced.
Hormone replacement therapy, thrombosis and thrombophilia
Authors: Keeling David M
Published: February 2006

Hormone replacement therapy increases the risk of venous thromboembolism. The risk is already increased in those with a personal or family history of thrombosis and in those with a hereditary thrombophilia. This article gives estimates of the absolute risk of using hormone replacement therapy and practical advice on its use in these groups and on the role of thrombophilia screening.
Homeopathy service in a National Health Service community menopause clinic: audit of clinical outcomes
Authors: Relton Clare , Weatherley-Jones Elaine
Published: February 2006

Sheffield's National Health Service community menopause clinic has run a homeopathy service since 1998. The service provides an alternative treatment option for those women who cannot take hormone replacement therapy, do not want it, have found it ineffective, or have been advised to stop it. Patients receive homeopathic treatment (monthly consultations plus individualized homeopathic medicines) for up to six sessions. An audit was undertaken of all patients referred to this service between 2001 and 2003, in which patients completed the Measure Yourself Medical Outcome Profile. Patients reported significant benefit from the service. The greatest response was seen in those reporting headaches, vasomotor symptoms, emotional/psychological symptoms and tiredness/fatigue as their primary symptoms.
Advances in the understanding and treatment of ovarian cancer
Authors: Morrison Jo
Published: February 2006

In England and Wales, ovarian cancer is responsible for more deaths than all other gynaecological cancers combined. Unlike cervical cancer, there is no effective population screening programme and the majority of women will present when the disease has spread beyond the ovaries. Current first-line management involves surgical debulking, followed by platinum-based chemotherapy. However, most women will relapse and the five-year survival rate is 20–30%. Novel therapies, based on an increasing understanding of the molecular biology of cancers, are being developed and evaluated in clinical trials.
Muscle performance after the menopause
Authors: Sirola Joonas , Rikkonen Toni
Published: February 2006

The timing of the menopause transition has remained fairly constant throughout history. It represents a milestone in female health and, after passing through it, women experience increased musculoskeletal and cardiovascular morbidity. Muscle performance is an important determinant of functional capacity and quality of life among the elderly and is also involved in the maintenance of balance. Therefore, good muscle strength can prevent fragility fractures and lessen the burden of osteoporosis. Muscle strength begins to decline during the perimenopausal years and this phenomenon seems to be partly estrogen dependent. Randomized controlled trials have indicated that hormone replacement therapy may prevent a decline in muscle performance, although the exact mechanism of estrogen-dependent sarcopenia remains to be clarified. Exercises have been shown to improve postmenopausal muscle performance and hormone replacement therapy may also potentiate these beneficial effects. Improvement or maintenance of muscle strength alone, however, may not be considered as a primary indication for long-term hormone replacement therapy in view of current knowledge of its risks and benefits. Work history and educational background may be associated with postmenopausal muscle performance, which itself has unique associations with skeletal and cardiovascular diseases.
Drug metabolism and ageing
Authors: Wynne Hilary
Published: February 2006

Older people are major consumers of drugs and because of this, as well as co-morbidity and age-related changes in pharmacokinetics and pharmacodynamics, are at risk of associated adverse drug reactions. While age does not alter drug absorption in a clinically significant way, and age-related changes in volume of drug distribution and protein binding are not of concern in chronic therapy, reduction in hepatic drug clearance is clinically important. Liver blood flow falls by about 35% between young adulthood and old age, and liver size by about 24–35% over the same period. First-pass metabolism of oral drugs avidly cleared by the liver and clearance of capacity-limited hepatically metabolized drugs fall in parallel with the fall in liver size, and clearance of drugs with a high hepatic extraction ratio falls in parallel with the fall in hepatic blood flow. In normal ageing, in general, activity of the cytochrome P450 enzymes is preserved, although a decline in frail older people has been noted, as well as in association with liver disease, cancer, trauma, sepsis, critical illness and renal failure. As the contribution of age, co-morbidity and concurrent drug therapy to altered drug clearance is impossible to predict in an individual older patient, it is wise to start any drug at a low dose and increase this slowly, monitoring carefully for beneficial and adverse effects.
Factors relating to depression after stroke
Authors: Thomas Shirley A. , Lincoln Nadina B.
Published: February 2006

Objectives. Depression is common after stroke and can impede rehabilitation. The aim of this study was to determine which factors predicted the severity of depression at the time of recruitment to a treatment study and depression 6 months later.

Design. A questionnaire‐based longitudinal study.

Methods. A total of 123 depressed stroke patients who were between 1 and 6 months post‐stroke and had mild to moderate disabilities were recruited to a randomized controlled trial of cognitive behavioural psychotherapy (CBT) to treat depression (Lincoln & Flannaghan, 2003). At recruitment and at 6 months follow‐up, patients (N=112) were assessed on the Beck Depression Inventory (BDI), General Health Questionnaire‐28 (GHQ‐28), Wakefield Depression Inventory (WDI), Barthel index, Extended activities of daily living scale (EADL), Sheffield Screening Test for Acquired Language Disorders (SST) and Recovery locus of control scale (RLOC).

Results. Logistic regression showed that greater communication impairment on the SST at recruitment was predictive of severe depression on the BDI at recruitment (OR=0.72, p=.01). Patients with greater communication impairment (OR=0.69, p<.05) and a more external locus of control (OR=0.89, p<.05) at recruitment were more likely to remain depressed at follow‐up. Patients who remained depressed at follow‐up were more severely depressed at recruitment (p=.001).

Conclusions. Locus of control and communication impairment were related to depression. Communication impairment was the strongest predictor of depression severity and prognosis. Mild depression was more likely to resolve. The regression models only accounted for a small proportion of the variance in depression scores. Therefore, further studies of psychosocial factors in a more representative sample are required.
Predicting Use of Non-Lethal Force in a Mid-Size Police Department: A Longitudinal Analysis of the Influence of Subject and Situational Variables
Authors: Leinfelt Fredrik H.
Published: February 2006

Historically, most research investigating use of non-lethal force predictors have found that certain subject characteristics increase the likelihood of non-lethal force occurring in a police–citizen encounter. Original police-reported use of force data ( N=3,673) was gathered over a period of 27 months in a Midwestern jurisdiction employing 50 sworn officers. The present dataset was unique in that it was not dependent upon whether an arrest was made. The present findings generally support the findings of studies conducted in larger urban police departments. For example, use of force is infrequent, suspects are more likely to have force used against them while resisting arrest, use of force is not consistently related to age, the likelihood of use of force increases when the suspect was male. This study failed to find that intoxication is a good predictor of non-lethal force. It was concluded that police use of non-lethal force is applied under similar circumstances regardless of community and department size.
Role Expectations of the Police: An Analysis of 50 State Statutes
Authors: Roncace Brenton , Giacomazzi Andrew , Hemmens Craig , Fliege Georg
Published: February 2006

While police scholars, practitioners and policy makers each have views on the primary roles of the police in society, their opinions tend to be diverse. Here, we have aimed to describe the current state of role expectations of the police from an analysis of 2002 statutes from all 50 US states. We have then compared our findings to those of Burton et al.'s (1993) similar study in an effort to determine change patterns in state statutes. The findings suggest that state laws from 2002 had a mixed law enforcement and peacekeeping approach to policing and provided more codified role expectations of the police than they did in 1993.
Police Reform: Problems of Governance and Accountability Management Challenges Surrounding Current Proposals for Police Restructuring
Authors: Loveday Barry
Published: February 2006

This article considers the current decision of the Home Secretary to scrap the 43 police forces and replace them with 12–15 regional strategic police forces. This follows on from the recent report of HMIC, entitled Closing the Gap, published in September 2005, which was to conclude that as currently constituted the police structure for England and Wales was no longer ‘fit for purpose’. Using the ability of police services to provide an effective response to NIM Level 2 crime as a yardstick, HMIC was to find that any force with fewer than 4,000 police officers would be unlikely to be able to provide an adequate response.

One consequence of the report and the Home Secretary's response to it has been the request made to all police authorities and forces to present a business case to the Home Office by the end of 2005 identifying the future structure of policing in the region and the pattern of amalgamation they might favour. In the course of this exercise it was to be found that alternatives to amalgamation, collaboration and federation, had both been closed down by the Home Secretary, who has concluded that only the option of amalgamation was now acceptable to his department.

Subsequently it was to be learned that a number of factors influencing HMIC's 2005 report obtained that had not been taken into account. These included the decision on the part of HMIC specifically not to include the written section on force collaboration within the final report. Nor, it was also to be discovered, had recognition been given within the report to the expectation that implementation was to be carried out in conjunction with comprehensive Workforce Modernisation. A leaked memorandum from ODPM in late 2005 that local government reform was now under active consideration was also to undermine the earlier assumption on the part of HMIC that no plans for local government reform were currently planned and that unilateral police reorganisation was therefore appropriate.
Osmolality Gaps: Diagnostic Accuracy and Long-Term Variability
Authors: Krahn John , Khajuria Annu
Published: February 2006

Background: The osmolal gap (OG) is a screening test for the detection of toxic volatiles such as methanol and ethylene glycol. We used mean values of patient data to assess the diagnostic accuracy and long-term stability of OG measurements.

Methods: In a prospective study period in 2003, all requests for volatiles had OGs calculated and quality-control samples were analyzed for OG. ROC curves were constructed to determine whether OG could predict the presence of toxic volatiles in serum. This was also done in a retrospective study for data from 1996 to 2004. Our laboratory database was searched for all emergency room patients for the period of 1996 to 2004 who had tests ordered that allowed us to calculate OGs.

Results: For the prospective study period in 2003, the ROC areas indicated that we could accurately predict the presence of toxic volatiles but at markedly different decision cutpoints depending on the formula used. These cutpoints ranged from +10 to +33 mosmol/kg. In the retrospective study, the mean OGs in the patient population for each of the 3 formulas increased by 12 mosmol/kg from 1996 to 2004. For this reason, the diagnostic accuracy was poor when all data were analyzed together.

Conclusions: Under properly controlled conditions, the OG has high sensitivity and specificity for detection of poisoning with some volatiles. Over the long term, however, use of the reference interval of −10 to +10 mosmol/kg yields poor diagnostic accuracy because mean OGs are not constant over time. Bedside calculation is not advisable.
Benchmark for Evaluating the Quality of DNA Sequencing: Proposal from an International External Quality Assessment Scheme
Authors: Patton Simon J , Wallace Andrew J , Elles Rob
Published: February 2006

Background: In the past 15 years, clinical laboratory science has been transformed by the use of technologies that cross the traditional boundaries between laboratory disciplines. However, during this period, issues of quality have not always been given adequate attention. The European Molecular Genetics Quality Network (EMQN) has developed a novel external quality assessment scheme for evaluation of DNA sequencing. We report the results of an international survey of the quality of DNA sequencing among 64 laboratories from 21 countries.

Methods: Current practice for DNA sequence analysis was established by use of an online questionnaire. Participating laboratories were provided with 4 DNA samples of validated genotype. Evaluation of the results included assessing the quality of sequence data, variant genotypes, and mutation nomenclature. To accommodate variations in mutation nomenclature, variants indicated by participants were scored for compliance with 3 acceptable marking schemes.

Results: A total of 346 genotypes were analyzed. Of these, 19 (5%) genotyping errors were made. Of these, 10 (53%) were false-negative and 9 (47%) were false-positive results. A further 27 (8%) errors were made in naming mutations. Results were analyzed for 3 indicators of data quality: PHRED quality scores, Quality Read Length, and Quality Read Overlap. Most laboratories produced results of acceptable diagnostic quality as judged by these indicators. The results were used to calculate a consensus benchmark for DNA sequencing against which individual laboratories could rank their performance.

Conclusions: We propose that the consensus benchmark can be used as a baseline against which the aggregate and individual laboratory standard of DNA sequencing may be tracked from year to year.
Proliferation and Death of Oligodendrocytes and Myelin Proteins Are Differentially Regulated in Male and Female Rodents
Authors: Cerghet Mirela , Skoff Robert P. , Bessert Denise , Zhang Zhan , Mullins Chadwick , Ghandour M. Said
Published: February 2006

Sexual dimorphism of neurons and astrocytes has been demonstrated in different centers of the brain, but sexual dimorphism of oligodendrocytes and myelin has not been examined. We show, using immunocytochemistry andin situhybridization, that the density of oligodendrocytes in corpus callosum, fornix, and spinal cord is 20–40% greater in males compared with females. These differences are present in young and aged rodents and are independent of strain and species. Proteolipid protein and carbonic anhydrase-II transcripts, measured by real-time PCR, are approximately two to three times greater in males. Myelin basic protein and 2′, 3′-cyclic nucleotide 3′-phosphodiesterase, measured by Western blots, are 20–160% greater in males compared with females. Surprisingly, both generation of new glia and apoptosis of glia, including oligodendrocytes, are approximately two times greater in female corpus callosum. These results indicate that the lifespan of oligodendrocytes is shorter in females than in males. Castration of males produces a female phenotype characterized by fewer oligodendrocytes and increased generation of new glia. These findings indicate that exogenous androgens differentially affect the lifespan of male and female oligodendrocytes, and they can override the endogenous production of neurosteroids. The data imply that turnover of myelin is greater in females than in males. μ-Calpain, a protease upregulated in degeneration of myelin, is dramatically increased at both transcriptional and translational levels in females compared with males. These morphological, molecular, and biochemical data show surprisingly large differences in turnover of oligodendrocytes and myelin between sexes. We discuss the potential significance of these differences to multiple sclerosis, a sexually dimorphic disease, whose progression is altered by exogenous hormones.
δ Subunit Susceptibility Variants E177A and R220H Associated with Complex Epilepsy Alter Channel Gating and Surface Expression of α4β2δ GABAAReceptors
Authors: Feng Hua-Jun , Kang Jing-Qiong , Song Luyan , Dibbens Leanne , Mulley John , Macdonald Robert L.
Published: February 2006

Most human idiopathic generalized epilepsies (IGEs) are polygenic, but virtually nothing is known of the molecular basis for any of the complex epilepsies. Recently, two GABAAreceptor δ subunit variants (E177A, R220H) were proposed as susceptibility alleles for generalized epilepsy with febrile seizures plus and juvenile myoclonic epilepsy. In human embryonic kidney 293T cells, recombinant hα1β2δ(E177A) and hα1β2δ(R220H) receptor currents were reduced, but the basis for the current reduction was not determined. We examined the mechanistic basis for the current reduction produced by these variants using the hα4β2δ receptor, an isoform more physiologically relevant and linked to epileptogenesis, by characterizing the effects of these variants on receptor cell surface expression and single-channel gating properties. Expression of variant α4β2δ(R220H) receptors resulted in a decrease in surface receptor proteins, and a smaller, but significant, reduction was observed for variant α4β2δ(E177A) receptors. For both variants, no significant alterations of surface expression were observed for mixed population of wild-type and variant receptors. The mean open durations of α4β2δ(E177A) and α4β2δ(R220H) receptor single-channel currents were both significantly decreased compared to wild-type receptors. These data suggest that both δ(E177A) and δ(R220H) variants may result in disinhibition in IGEs by similar cellular and molecular mechanisms, and in heterozygously affected individuals, a reduction in channel open duration of δ subunit-containing GABAAreceptors may be the major contributor to the epilepsy phenotypes.
The Endocannabinoid System Promotes Astroglial Differentiation by Acting on Neural Progenitor Cells
Authors: Aguado Tania , Palazuelos Javier , Monory Krisztina , Stella Nephi , Cravatt Benjamin , Lutz Beat , Marsicano Giovanni , Kokaia Zaal , Guzmán Manuel , Galve-Roperh Ismael
Published: February 2006

Endocannabinoids exert an important neuromodulatory role via presynaptic cannabinoid CB1receptors and may also participate in the control of neural cell death and survival. The function of the endocannabinoid system has been extensively studied in differentiated neurons, but its potential role in neural progenitor cells remains to be elucidated. Here we show that the CB1receptor and the endocannabinoid-inactivating enzyme fatty acid amide hydrolase are expressed, bothin vitroandin vivo, in postnatal radial glia (RC2+cells) and in adult nestin type I (nestin+GFAP+) neural progenitor cells. Cell culture experiments show that CB1receptor activation increases progenitor proliferation and differentiation into astroglial cellsin vitro.In vivoanalysis evidences that, in postnatalCB1−/−mouse brain, progenitor proliferation and astrogliogenesis are impaired. Likewise, in adult CB1-deficient mice, neural progenitor proliferation is decreased but is increased in fatty acid amide hydrolase-deficient mice. In addition, endocannabinoid signaling controls neural progenitor differentiation in the adult brain by promoting astroglial differentiation of newly born cells. These results show a novel physiological role of endocannabinoids, which constitute a new family of signaling cues involved in the regulation of neural progenitor cell function.
Between-Task Competition and Cognitive Control in Task Switching
Authors: Yeung Nick , Nystrom Leigh E. , Aronson Jessica A. , Cohen Jonathan D.
Published: February 2006

Cognitive control is required to regulate interactions between brain regions to produce effective, purposeful behavior. We used functional magnetic resonance imaging to investigate the nature of these interactions and the role of prefrontal cortex (PFC) in cognitive control as subjects switched between simple face and word categorization tasks. Face and word stimuli were used because previous research has shown them to activate distinguishable cortical regions, allowing us to measure levels of activity in task-selective brain regions during task switching. We found that activity in brain regions selective for the currently irrelevant task predicted the behavioral cost associated with switching tasks. This finding supports the theory that between-task competition is a critical determinant of behavior. Task switching was also associated with increased activity in a network of regions implicated in cognitive control, including lateral PFC and parietal cortex. Within this network of regions, we observed dissociations between task-selective and general purpose mechanisms. These findings provide support for theories that propose a control hierarchy comprising regions responsible for maintaining task-specific information about rules or goals, and regions involved in the coordination of these goals.
Alzheimer Precursor Protein Interaction with the Nogo-66 Receptor Reduces Amyloid-β Plaque Deposition
Authors: Park James H. , Gimbel David A. , GrandPre Tadzia , Lee Jung-Kil , Kim Ji-Eun , Li Weiwei , Lee Daniel H. S. , Strittmatter Stephen M.
Published: February 2006

Pathophysiologic hypotheses for Alzheimer’s disease (AD) are centered on the role of the amyloid plaque Aβ peptide and the mechanism of its derivation from the amyloid precursor protein (APP). As part of the disease process, an aberrant axonal sprouting response is known to occur near Aβ deposits. A Nogo to Nogo-66 receptor (NgR) pathway contributes to determining the ability of adult CNS axons to extend after traumatic injuries. Here, we consider the potential role of NgR mechanisms in AD. Both Nogo and NgR are mislocalized in AD brain samples. APP physically associates with the NgR. Overexpression of NgR decreases Aβ production in neuroblastoma culture, and targeted disruption of NgR expression increases transgenic mouse brain Aβ levels, Aβ plaque deposition, and dystrophic neurites. Infusion of a soluble NgR fragment reduces Aβ levels, amyloid plaque deposits, and dystrophic neurites in a mouse transgenic AD model. Changes in NgR level produce parallel changes in secreted APPα and Aβ, implicating NgR as a blocker of secretase processing of APP. The NgR provides a novel site for modifying the course of AD and highlights the role of axonal dysfunction in the disease.
The Dopaminergic Midbrain Participates in Human Episodic Memory Formation: Evidence from Genetic Imaging
Authors: Schott Björn H. , Seidenbecher Constanze I. , Fenker Daniela B. , Lauer Corinna J. , Bunzeck Nico , Bernstein Hans-Gert , Tischmeyer Wolfgang , Gundelfinger Eckart D. , Heinze Hans-Jochen , Düzel Emrah
Published: February 2006

Recent data from animal studies raise the possibility that dopaminergic neuromodulation promotes the encoding of novel stimuli. We investigated a possible role for the dopaminergic midbrain in human episodic memory by measuring how polymorphisms in dopamine clearance pathways affect encoding-related brain activity (functional magnetic resonance imaging) in an episodic memory task. In 51 young, healthy adults, successful episodic encoding was associated with activation of the substantia nigra. This midbrain activation was modulated by a functional variable number of tandem repeat (VNTR) polymorphism in the dopamine transporter (DAT1) gene. Despite no differences in memory performance between genotype groups, carriers of the (low expressing) 9-repeat allele of the DAT1 VNTR showed relatively higher midbrain activation when compared with subjects homozygous for the 10-repeat allele, who express DAT1 at higher levels. The catechol-O-methyl transferase (COMT) Val108/158Met polymorphism, which is known to modulate enzyme activity, affected encoding-related activity in the right prefrontal cortex (PFC) and in occipital brain regions but not in the midbrain. Moreover, subjects homozygous for the (low activity) Met allele showed stronger functional coupling between the PFC and the hippocampus during encoding. Our finding that genetic variations in the dopamine clearance pathways affect encoding-related activation patterns in midbrain and PFC provides strong support for a role of dopaminergic neuromodulation in human episodic memory formation. It also supports the hypothesis of anatomically and functionally distinct roles for DAT1 and COMT in dopamine metabolism, with DAT1 modulating rapid, phasic midbrain activity and COMT being particularly involved in prefrontal dopamine clearance.
Inhibition of Calcineurin by FK506 Protects against Polyglutamine-Huntingtin Toxicity through an Increase of Huntingtin Phosphorylation at S421
Authors: Pardo Raúl , Colin Emilie , Régulier Etienne , Aebischer Patrick , Déglon Nicole , Humbert Sandrine , Saudou Frédéric
Published: February 2006

Huntington’s disease (HD) is caused by an abnormal expanded polyglutamine (polyQ) repeat in the huntingtin protein. Insulin-like growth factor-1 acting through the prosurvival kinase Akt mediates the phosphorylation of huntingtin at S421 and inhibits the toxicity of polyQ-expanded huntingtin in cell culture, suggesting that compounds enhancing phosphorylation are of therapeutic interest. However, it is not clear whether phosphorylation of S421 is crucialin vivo. Using a rat model of HD based on lentiviral-mediated expression of a polyQ-huntingtin fragment in the striatum, we demonstrate here that phosphorylation of S421 is neuroprotectivein vivo. We next demonstrate that calcineurin (CaN), a calcium/calmodulin-regulated Ser/Thr protein phosphatase, dephosphorylates S421in vitroand in cells. Inhibition of calcineurin activity, either by overexpression of the dominant-interfering form of CaN or by treatment with the specific inhibitor FK506, favors the phosphorylation of S421, restores the alteration in huntingtin S421 phosphorylation in HD neuronal cells, and prevents polyQ-mediated cell death of striatal neurons. Finally, we show that administration of FK506 to mice increases huntingtin S421 phosphorylation in brain. Collectively, these data highlight the importance of CaN in the modulation of S421 phosphorylation and suggest the potential use of CaN inhibition as a therapeutic approach to treat HD.
The Androgen 5α-Dihydrotestosterone and Its Metabolite 5α-Androstan-3β, 17β-Diol Inhibit the Hypothalamo–Pituitary–Adrenal Response to Stress by Acting through Estrogen Receptor β-Expressing Neurons in the Hypothalamus
Authors: Lund Trent D. , Hinds Laura R. , Handa Robert J.
Published: February 2006

Estrogen receptor β (ERβ) and androgen receptor (AR) are found in high levels within populations of neurons in the hypothalamus. To determine whether AR or ERβ plays a role in regulating hypothalamo–pituitary–adrenal (HPA) axis function by direct action on these neurons, we examined the effects of central implants of 17β-estradiol (E2), 5α-dihydrotestosterone (DHT), the DHT metabolite 5α-androstan-3β, 17β-diol (3β-diol), and several ER subtype-selective agonists on the corticosterone and adrenocorticotropin (ACTH) response to immobilization stress. In addition, activation of neurons in the paraventricular nucleus (PVN) was monitored by examining c-fos mRNA expression. Pellets containing these compounds were stereotaxically implanted near the PVN of gonadectomized male rats. Seven days later, animals were killed directly from their home cage (nonstressed) or were restrained for 30 min (stressed) before they were killed. Compared with controls, E2 and the ERα-selective agonists moxestrol and propyl-pyrazole-triol significantly increased the stress induced release of corticosterone and ACTH. In contrast, central administration of DHT, 3β-diol, and the ERβ-selective compound diarylpropionitrile significantly decreased the corticosterone and ACTH response to immobilization. Cotreatment with the ER antagonist tamoxifen completely blocked the effects of 3β-diol and partially blocked the effect of DHT, whereas the AR antagonist flutamide had no effect. Moreover, DHT, 3β-diol, and diarylpropionitrile treatment significantly decreased restraint-induced c-fos mRNA expression in the PVN. Together, these studies indicate that the inhibitory effects of DHT on HPA axis activity may be in part mediated via its conversion to 3β-diol and subsequent binding to ERβ.
The Dopamine D3Receptor Is Part of a Homeostatic Pathway Regulating Ethanol Consumption
Authors: Jeanblanc Jerome , He Dao-Yao , McGough Nancy N. H. , Logrip Marian L. , Phamluong Khanhky , Janak Patricia H. , Ron Dorit
Published: February 2006

We recently identified a homeostatic pathway that inhibits ethanol intake. This protective pathway consists of the scaffolding protein RACK1 and brain-derived neurotrophic factor (BDNF). RACK1 translocates to the nucleus after exposure of neurons to ethanol and increases expression of BDNF (McGough et al., 2004). We also found that increasing the levels of BDNF via systemic administration of RACK1 expressed as a Tat-fusion protein (Tat–RACK1) reduces ethanol consumption, whereas reduction of BDNF levels augments this behavior (McGough et al., 2004). Based on these results, we hypothesized that activation of the BDNF receptor TrkB is necessary for the effects of BDNF on ethanol intake and that gene products downstream of BDNF negatively regulate ethanol consumption. Here, we show that inhibition of the BDNF receptor TrkB increases voluntary ethanol consumption in wild-type mice but not in mice lacking one copy of the BDNF gene (BDNF+/−). We also find that increases in the levels ofBDNF, mediated by ethanol or RACK1, lead to increased dorsal striatal levels of the dopamineD3receptor(D3R), a gene downstream of BDNF, via activation of the TrkB receptor. Finally, we show that the Tat–RACK1-mediated reduction of ethanol consumption is attenuated by coinjection with either the Trk inhibitor K252a or the dopamine D3R-prefering antagonist U-99194A [5, 6-dimethoxy-2-(di-n-propylamino)indan], suggesting that activation of the BDNF pathway via RACK1 leads to increased expression of the dopamine D3R, which in turn mediates the attenuation of ethanol consumption.
Physiological Temperatures Reduce the Rate of Vesicle Pool Depletion and Short-Term Depression via an Acceleration of Vesicle Recruitment
Authors: Kushmerick Christopher , Renden Robert , von Gersdorff Henrique
Published: February 2006

The timing and strength of synaptic transmission is profoundly dependent on temperature. However, the temperature dependence of the multiple mechanisms that contribute to short-term synaptic plasticity is poorly understood. Here, we use voltage-clamp recordings to quantify the temperature dependence of exocytosis at the calyx of Held synapse. EPSC and miniature EPSC amplitudes were larger at physiological temperature, but quantal content during low-frequency (0.05 Hz) stimulation was constant after temperature jumps from 22–24°C to 35–37°C. The initial degree of EPSC depression during 100 Hz stimuli trains was unchanged with temperature, as were estimates of release probability and vesicle pool size. In contrast, physiological temperatures dramatically relieved depression measured after 40 stimuli at 100 Hz by increasing twofold the rate of recovery from depression. Presynaptic calyx recordings revealed that physiological temperature increased capacitance jumps resulting from 0.5 and 1 ms depolarizations by increasing Ca2+influx. When Ca2+entry was equalized at the two temperatures, exocytosis exhibited little temperature dependence for brief depolarizations. However, in response to longer depolarizations, raising temperature increased a slow phase of exocytosis, without affecting overall Ca2+entry or the size of the readily releasable pool of vesicles. Higher temperatures also increased the rate of presynaptic Ca2+current inactivation; nevertheless, the degree of steady-state EPSC depression was greatly reduced. Our results thus suggest that changes in steady-state EPSCs during stimulus trains at physiological temperature reflect larger quantal amplitudes and faster refilling of synaptic vesicle pools, leading to reduced short-term depression during prolonged high-frequency firing.
P2X7Receptors Mediate ATP Release and Amplification of Astrocytic Intercellular Ca2+Signaling
Authors: Suadicani Sylvia O. , Brosnan Celia F. , Scemes Eliana
Published: February 2006

Modulation of synaptic transmission and brain microcirculation are new roles ascribed to astrocytes in CNS function. A mechanism by which astrocytes modify neuronal activity in the healthy brain depends on fluctuations of cytosolic Ca2+levels, which regulate the release of “gliotransmitters” via an exocytic pathway. Under pathological conditions, however, the participation of other pathways, including connexin hemichannels and the pore-forming P2X7R, have been proposed but remain controversial. Through the use of genetically modified 1321N1 human astrocytoma cells and of spinal cord astrocytes derived from neonatal Cx43- and P2X7R-null mice, we provide strong evidence that P2X7Rs, but not Cx43 hemichannels, are sites of ATP release that promote the amplification of Ca2+signal transmission within the astrocytic network after exposure to low divalent cation solution. Moreover, our results showing that gap junction channel blockers (heptanol, octanol, carbenoxolone, flufenamic acid, and mefloquine) are antagonists of the P2X7R indicate the inadequacy of using these compounds as evidence for the participation of connexin hemichannels as sites of gliotransmitter release.
Cocaine Increases Actin Cycling: Effects in the Reinstatement Model of Drug Seeking
Authors: Toda Shigenobu , Shen Hao-Wei , Peters Jamie , Cagle Stephanie , Kalivas Peter W.
Published: February 2006

Addiction to cocaine is associated with persistent changes in synaptic function. The cycling of actin between polymerized [F (for filamentous)] and depolymerized forms contributes to synaptic plasticity, and acute and withdrawal from repeated cocaine administration produced reversible and enduring elevations, respectively, in F-actin in the nucleus accumbens. Increased F-actin after 3 weeks withdrawal from repeated cocaine resulted from changes in the content or phosphorylation state of actin binding proteins (ABPs) that cosediment with F-actin. The profile of altered APBs was consistent with filopodia formation, including increased mammalian Enabled, phosphorylated (p)-cortactin, and p-vasodilator-stimulated phosphoprotein, and increased actin depolymerization [e.g., reduced LIM (Lin11/Isl-1/Mec3)-kinase and p-cofilin]. In contrast to repeated cocaine, the increase in F-actin after acute cocaine administration resulted from reduced depolymerization and actin cycling. The potential involvement of chronic cocaine-induced increases in actin cycling in cocaine addiction was examined using the reinstatement of cocaine seeking in rats previously trained to self-administer cocaine by inhibiting actin polymerization with intra-accumbens latrunculin A or by accelerating actin depolymerization with a LIM-kinase inhibitor. Disrupting actin cycling via either mechanism augmented cocaine-induced reinstatement of drug seeking but did not affect the locomotor response to acute cocaine administration. Thus, withdrawal from repeated cocaine induces a restructuring of actin–ABP complexes, which increases actin cycling and may modulate cocaine-induced reinstatement of drug seeking.
Regulation of the Neuronal Proteasome by Zif268 (Egr1)
Authors: James Allan B. , Conway Ann-Marie , Morris Brian J.
Published: February 2006

Most forms of neuronal plasticity are associated with induction of the transcription factor Zif268 (Egr1/Krox24/NGF-IA). In a genome-wide scan, we obtained evidence for potential modulation of proteasome subunit and regulatory genes by Zif268 in neurons, a finding of significance considering emerging evidence that the proteasome modulates synaptic function. Bioinformatic analysis indicated that the candidate proteasome Zif268 target genes had a rich concentration of putative Zif268 binding sites immediately upstream of the transcriptional start sites. Regulation of the mRNAs encoding the psmb9 (Lmp2) and psme2 (PA28β) proteasome subunits, along with the proteasome-regulatory kinase serum/glucocorticoid-regulated kinase (SGK) and the proteasome-associated antigen peptide transporter subunit 1 (Tap1), was confirmed after transfection of a neuronal cell line with Zif268. Conversely, these mRNAs were upregulated in cerebral cortex tissue fromZif268knock-out mice relative to controls, confirming that Zif268 suppresses their expression in the CNS. Transfected Zif268 reduced the activity ofpsmb9,SGK, andTap1promoter–reporter constructs. Alteredpsmb9,SGK, andTap1mRNA levels were also observed in anin vivomodel of neuronal plasticity involving Zif268 induction: the effect of haloperidol administration on striatal gene expression. Consistent with these effects on proteasome gene expression, increased Zif268 expression suppressed proteasome activity, whereasZif268knock-out mice exhibited elevated cortical proteasome activity. Our findings reveal that Zif268 regulates the expression of proteasome and related genes in neuronal cells and provide new evidence that altered expression of proteasome activity after Zif268 induction may be a key component of long-lasting CNS plasticity.
Rac1 and RhoA Promote Neurite Outgrowth through Formation and Stabilization of Growth Cone Point Contacts
Authors: Woo Stephanie , Gomez Timothy M.
Published: February 2006

Growth cone advance depends on coordinated membrane protrusion and adhesion to the extracellular matrix. Although many studies have addressed the mechanisms responsible for membrane protrusion, the assembly of integrin-dependent adhesion sites known as point contacts remains poorly understood in growth cones. We show balanced Rac1 activity controls both leading edge protrusion and point contact dynamics during neurite outgrowth. Immunocytochemistry and live imaging of paxillin–green fluorescent protein (GFP) showed that inhibiting Rac1 blocked point contact formation, whereas Rac1 overactivation produced small, unstable point contacts. Both inhibition and overactivation of Rac1 reduced the persistence of lamellar protrusions and neurite outgrowth. Inhibition of ROCK (Rho kinase), a RhoA effector, perturbed protrusion and point contact dynamics similar to Rac1 overactivation. Moreover, the repulsive guidance cue Semaphorin 3A, which signals through Rac1, destabilizes point contacts. Together, our data suggest that coordinated Rho GTPase activities regulate neurite outgrowth through point contact formation and stabilization of membrane protrusion.
Locus Ceruleus Degeneration Promotes Alzheimer Pathogenesis in Amyloid Precursor Protein 23 Transgenic Mice
Authors: Heneka Michael T. , Ramanathan Mutiah , Jacobs Andreas H. , Dumitrescu-Ozimek Lucia , Bilkei-Gorzo Andras , Debeir Thomas , Sastre Magdalena , Galldiks Norbert , Zimmer Andreas , Hoehn Mathias , Heiss Wolf-Dieter , Klockgether Thomas , Staufenbiel Matthias
Published: February 2006

Locus ceruleus (LC) degeneration and loss of cortical noradrenergic innervation occur early in Alzheimer’s disease (AD). Although this has been known for several decades, the contribution of LC degeneration to AD pathogenesis remains unclear. We induced LC degeneration withN-(2-chloroethyl)-N-ethyl-bromo-benzylamine (dsp4) in amyloid precursor protein 23 (APP23) transgenic mice with a low amyloid load. Then 6 months later the LC projection areas showed a robust elevation of glial inflammation along with augmented amyloid plaque deposits. Moreover, neurodegeneration and neuronal loss significantly increased. Importantly, the paraventricular thalamus, a nonprojection area, remained unaffected. Radial arm maze and social partner recognition tests revealed increased memory deficits while high-resolution magnetic resonance imaging-guided micro-positron emission tomography demonstrated reduced cerebral glucose metabolism, disturbed neuronal integrity, and attenuated acetylcholinesterase activity. Nontransgenic mice with LC degeneration were devoid of these alterations. Our data demonstrate that the degeneration of LC affects morphology, metabolism, and function of amyloid plaque-containing higher brain regions in APP23 mice. We postulate that LC degeneration substantially contributes to AD development.
Fornix Lesions Decouple the Induction of Hippocampal Arc Transcription from Behavior But Not Plasticity
Authors: Fletcher Bonnie R. , Calhoun Michael E. , Rapp Peter R. , Shapiro Matthew L.
Published: February 2006

The immediate-early gene (IEG) Arc is transcribed after behavioral and physiological treatments that induce synaptic plasticity and is implicated in memory consolidation. The relative contributions of neuronal activity and learning-related plasticity to the behavioral induction of Arc remain to be defined. To differentiate the contributions of each, we assessed the induction of Arc transcription in rats with fornix lesions that impair hippocampal learning yet leave cortical connectivity and neuronal firing essentially intact. Arc expression was assessed after exploration of novel environments and performance of a novel water maze task during which normal rats learned the spatial location of an escape platform. During the same task, rats with fornix lesions learned to approach a visible platform but did not learn its spatial location. Rats with fornix lesions had normal baseline levels of hippocampal Arc mRNA, but unlike normal rats, expression was not increased in response to water maze training. The integrity of signaling pathways controlling Arc expression was demonstrated by stimulation of the medial perforant path, which induced normal synaptic potentiation and Arc in rats with fornix lesions. Together, the results demonstrate that Arc induction can be decoupled from behavior and is more likely to indicate the engagement of synaptic plasticity mechanisms than synaptic or neuronal activity per se. The results further imply that fornix lesions may impair memory in part by decoupling neuronal activity from signaling pathways required for long-lasting hippocampal synaptic plasticity.
Chronic Stress Increases the Plasmalemmal Distribution of the Norepinephrine Transporter and the Coexpression of Tyrosine Hydroxylase in Norepinephrine Axons in the Prefrontal Cortex
Authors: Miner LeeAnn H. , Jedema Hank P. , Moore Forrest W. , Blakely Randy D. , Grace Anthony A. , Sesack Susan R.
Published: February 2006

Norepinephrine (NE) potently modulates the cognitive and affective functions of the prefrontal cortex (PFC). Deficits in NE transmission are implicated in psychiatric disorders, and antidepressant drugs that block the NE transporter (NET) effectively treat these conditions. Our initial ultrastructural studies of the rat PFC revealed that most NE axons (85–90%) express NET primarily within the cytoplasm and lack detectable levels of the synthetic enzyme tyrosine hydroxylase (TH). In contrast, the remaining 10–15% of PFC NE axons exhibit predominantly plasmalemmal NET and evident TH immunoreactivity. These unusual characteristics suggest that most PFC NE axons have an unrecognized, latent capacity to enhance the synthesis and recovery of transmitter. In the present study, we used dual-labeling immunocytochemistry and electron microscopy to examine whether chronic cold stress, a paradigm that persistently increases NE activity, would trigger cellular changes consistent with this hypothesis. After chronic stress, neither the number of profiles exhibiting NET labeling nor their size was changed. However, the proportion of plasmalemmal NET nearly doubled from 29% in control animals to 51% in stressed rats. Moreover, the expression of detectable TH in NET-labeled axons increased from only 13% of profiles in control rats to 32% of profiles in stressed animals. Despite the consistency of these findings, the magnitude of the changes varied across individual rats. These data represent the first demonstration of activity-dependent trafficking of NET and expression of TH under physiological conditions and have important implications for understanding the pathophysiology and treatment of stress-related affective disorders.
Long-Term Adeno-Associated Viral Vector-Mediated Expression of Truncated TrkB in the Adult Rat Facial Nucleus Results in Motor Neuron Degeneration
Authors: De Wit Joris , Eggers Ruben , Evers Robert , Castrén Eero , Verhaagen Joost
Published: February 2006

Adult facial motor neurons continue to express full-length TrkB tyrosine kinase receptor (TrkB.FL), the high-affinity receptor for the neurotrophins BDNF and neurotrophic factor-4/5 (NT-4/5), suggesting that they remain dependent on target-derived and locally produced neurotrophins in adulthood. Studies on the role of TrkB signaling in the adult CNS have been hampered by the early lethality ofbdnf,nt-4/5, andtrkBknock-out mice. We disrupted TrkB.FL signaling in adult facial motor neurons using adeno-associated viral vector-mediated overexpression of a naturally occurring dominant-negative TrkB receptor, TrkB.T1. Expression of TrkB.T1 resulted in neuronal atrophy and downregulation of NeuN (neuronal-specific nuclear protein) and ChAT expression in facial motor neurons. A subset of transduced neurons displayed signs of motor neuron degeneration that included dendritic beading and rounding of the soma at 2 months of TrkB.T1 expression. Cell counts revealed a significant reduction in motor neuron number in the facial nucleus at 4 months after onset of expression of TrkB.T1, suggesting that a proportion of TrkB.T1-expressing motor neurons became undetectable as a result of severe atrophy or was lost because of cell death. In contrast, overexpression of TrkB.FL did not result in a decrease in facial motor neuron number. Our results indicate that a subset of facial motor neurons remains dependent on TrkB ligands for the maintenance of structural and molecular characteristics in adulthood.