bluuebunny/crossref_metadata_2025 huggingface dataset:
Methylenetetrahydrofolate reductase polymorphism (C677T), hyperhomocysteinemia, and risk of ischemic cardiovascular disease and venous thromboembolism: prospective and case-control studies from the Copenhagen City Heart Study
Authors: Frederiksen Jeppe , Juul Klaus , Grande Peer , Jensen Gorm B. , Schroeder Torben V. , Tybjærg-Hansen Anne , Nordestgaard Børge G.
Published: June 2004

Hyperhomocysteinemia is associated with ischemic cardiovascular disease (ICD) and venous thromboembolism (VTE). We tested the hypothesis that methylenetetrahydrofolate reductase (MTHFR) C677T homozygosity with hyperhomocysteinemia is associated with ICD and VTE. First, 9238 randomly selected whites from the general population were followed for 23 years. Second, 2125 whites with ischemic heart disease and 836 whites with ischemic cerebrovascular disease were compared with 7568 controls from the general population. Plasma homocysteine was elevated 25% in homozygotes versus noncarriers (P < .001) and 19% in ICD/VTE cases versus controls (P < .001). In prospective studies adjusted hazard ratios for ICD and VTE for homozygotes versus noncarriers did not differ from 1.0. Furthermore, MTHFR C677T homozygosity was not associated with increased risk of ICD or VTE in subgroups after stratification for sex, age, cholesterol, high-density lipoprotein cholesterol, lipoprotein(a), fibrinogen, triglycerides, body mass index, smoking, diabetes mellitus, hypertension, and factor V Leiden genotype. Finally, in case-control studies odds ratios for ischemic heart disease and ischemic cerebrovascular disease in homozygotes versus noncarriers did not differ from 1.0. In conclusion, MTHFR C677T homozygosity with hyperhomocysteinemia is not associated with ICD or VTE; however, ICD/VTE is associated with hyperhomocysteinemia. Therefore, ICD and VTE may cause hyperhomocysteinemia, rather than vice versa.
Kinetics of engraftment in patients with hematologic malignancies given allogeneic hematopoietic cell transplantation after nonmyeloablative conditioning
Authors: Baron Frédéric , Baker Jennifer E. , Storb Rainer , Gooley Theodore A. , Sandmaier Brenda M. , Maris Michael B. , Maloney David G. , Heimfeld Shelly , Oparin Dmitrij , Zellmer Eustacia , Radich Jerald P. , Grumet F. Carl , Blume Karl G. , Chauncey Thomas R. , Little Marie-Térèse
Published: June 2004

We analyzed the kinetics of donor engraftment among various peripheral blood cell subpopulations and their relationship to outcomes among 120 patients with hematologic malignancies given hematopoietic cell transplantation (HCT) after nonmyeloablative conditioning consisting of 2 Gy total body irradiation (TBI) with or without added fludarabine. While patients rapidly developed high degrees of donor engraftment, most remained mixed donor/host chimeras for up to 180 days after HCT. Patients given preceding chemotherapies and those given granulocyte colony-stimulating factor–mobilized peripheral blood mononuclear cell (G-PBMC) grafts had the highest degrees of donor chimerism. Low donor T-cell (P = .003) and natural killer (NK) cell (P = .004) chimerism levels on day 14 were associated with increased probabilities of graft rejection. High T-cell chimerism on day 28 was associated with an increased probability of acute graft-versus-host disease (GVHD) (P = .02). Of 93 patients with measurable malignant disease at transplantation, 41 achieved complete remissions a median of 199 days after HCT; 19 of the 41 were mixed T-cell chimeras when complete remissions were achieved. Earlier establishment of donor NK-cell chimerism was associated with improved progression-free survival (P = .02). Measuring the levels of peripheral blood cell subset donor chimerisms provided useful information on HCT outcomes and might allow early therapeutic interventions to prevent graft rejection or disease progression.
Molecular interactions involved in HOXB4-induced activation of HSC self-renewal
Authors: Beslu Nathalie , Krosl Jana , Laurin Mélanie , Mayotte Nadine , Humphries Keith R. , Sauvageau Guy
Published: June 2004

HOXB4 overexpression induces unique in vivo and in vitro expansion of hemopoietic stem cells (HSCs) without causing leukemia. Very little is known about the molecular basis underlying HOXB4-induced HSC self-renewal. We now report the in vitro proliferation and in vivo expansion capacity of primary bone marrow (BM) cells engineered to overexpress selected HOXB4 point mutants lacking either the capacity to directly bind DNA (HOXB4(A)), or to cooperate with members of the PBX family (HOXB4(W→G)) in DNA binding. The DNA binding–incompetent HOXB4 mutant failed to enhance the proliferation activity of transduced BM populations in vitro and HSC expansion in vivo. In contrast, the HOXB4(W→G) mutant conferred a pronounced in vitro proliferation advantage to the transduced BM populations, and dramatically enhanced their in vivo regenerative potential. We also demonstrate a correlation between HOXB4 protein levels and in vitro proliferative capacity of primary BM cells. Our observations thus suggest that the capacity of HOXB4 to induce HSC expansions is DNA-binding dependent and does not require direct HOX/PBX interaction, and sets the stage for identifying HOXB4-dependent targets involved in HSC expansion.
Attention-deficit hyperactivity disorder in adults: validity unknown1
Authors: Zwi Morris , York Ann
Published: June 2004

Attention-deficit hyperactivity disorder (ADHD) is a commonly diagnosed childhood psychiatric disorder. Debate over its diagnostic validity, aetiology, presentation and treatment has extended from the clinical to the public domain. As children with ADHD diagnoses reach adulthood there is increasing interest in ‘adult ADHD’. Cohorts followed up show poorer outcomes as adults than do controls. Self-referred adults, sometimes relatives of children with ADHD, are also of interest regarding adult ADHD. Innovative work is being done examining issues of aetiology, treatment, outcomes and comorbidity in these groups, but heterogeneity among those diagnosed with ADHD and changes in classification systems and diagnostic criteria over time complicate comparison of research findings. The diagnostic validity of adult ADHD remains uncertain and needs further study.
Bridging the service divide
Authors: Asherson Philip P.
Published: June 2004

Most child and adolescent mental health services recognise the existence of, and need for treatment in, attention-deficit hyperactivity disorder (ADHD). Many specialist multidisciplinary ADHD clinics have been developed in recent years, and many paediatricians have included the treatment of ADHD as an important part of their clinical activity. A good deal of the justification for this increase in therapeutic activity has been the demonstration that ADHD is indeed a predictor of adult mental health problems. General adult psychiatry, however, has not followed suit in identifying and treating substantial numbers of affected people. It is likely none the less that an increasing load in adult psychiatry will develop. A rising number of young people will enter adult life still receiving stimulant medication or other treatment for ADHD, and adult psychiatrists are likely to be consulted. Furthermore, an increasing number of adults are likely to recognise themselves as having been disabled by ADHD and therefore to seek assistance. In many cases, individuals with adult ADHD who require specific treatment for the condition will have been treated unsuccessfully for disorders with overlapping symptom profiles such as anxiety, depression, bipolar disorder and antisocial personality disorder.
Risk: more questions than answers
Authors: Holloway Frank
Published: June 2004

The rise of the risk industry in psychiatry in England and Wales can be given a precise date: 17 December 1992. That was the day that Christopher Clunis, a man who had been in contact with psychiatric services for some 6 years, murdered Jonathan Zito in an unprovoked attack. This tragedy received enormous publicity and resulted in a flurry of activity within the Department of Health. As a result of the moral panic surrounding Clunis, which crystallised long-term trends, the assessment and management of risk became a central focus of mental health policy and practice (Holloway, 1996). Risk remains a core issue, and indeed mental health services have come to be seen as a key element in a strategy for public protection that aims to keep people who are identified as a potential risk to others off the streets. (We await, with some professional trepidation, the legislation that will provide a sufficiently broad definition of mental illness to fully legitimate this social role.) Mental health staff are now required by government policy and their employers to assess an ever-expanding range of risks – most recently, following the Victoria Climbié Inquiry (House of Commons Health Committee, 2003), risks to dependent children, generally with the aid of unvalidated risk assessment tools. Increasingly, mainstream mental health services are being expected to provide interventions for people whose presenting problems are risky behaviours (or even risky feelings) rather than to offer treatment for mental illness.
Working with patients with religious beliefs1
Authors: Dein Simon
Published: June 2004

Mental health professionals in Western societies are generally less religious than their patients and receive little training in religious issues. Using case studies, the author discusses issues involved in working with patients who hold religious beliefs: problems of engagement; countertransference; religious and spiritual issues not attributable to mental disorder; problems of differential diagnosis; religious delusions; religion and psychotherapy; psychosexual problems; and religiously oriented treatments. The article ends with a discussion of the various ways in which religious themes can be incorporated into mental health work, especially the need to involve religious professionals and develop collaborative patterns of working together with mental health professionals.
Epidemiological medicine's best-kept secret?
Authors: Sims Andrew
Published: June 2004

Even to have a paper on working with patients with religious beliefs in a psychiatric journal is a liberating experience, and Dr Dein (2004, this issue) has dealt with his subject with thoroughness and fair-mindedness. We have come a long way since the standard British textbook of psychiatry in the 1960s (Mayer-Gross et al, 1960) could state that religion is for ‘the hesitant, the guilt-ridden, the excessively timid, those lacking clear convictions with which to face life’. At that time religious belief in patients was equated with neurosis, and in trainees in psychiatry it was regarded as being seriously unscientific and was strongly discouraged.
Aromatherapy in dementia
Authors: Holmes Clive , Ballard Clive
Published: June 2004

The use of plant essential oils in aromatherapy has been recorded for thousands of years, but until recently there was very little formal evidence regarding the use of these treatments in people with dementia. Over the past few years a number of clinical trials have compared aromatherapy, principally using either lavender (Lavandula angustifolia or Lavandula officinalis) or lemon balm (Melissa officinalis), with inactive treatment. All of these studies demonstrated a significant impact on behavioural problems in patients with dementia, with negligible side-effects. However, there is still not sufficient evidence to recommend widespread use in clinical practice and the key question of whether these treatments can provide a viable alternative to existing pharmacological agents needs to be addressed.
Improving safety in medicine: A systems approach
Authors: Munro Eileen
Published: June 2004

The statutory inquiries after homicides by people with mental illness have been replaced by a system of mandatory reporting to the newly established National Patient Safety Agency (Department of Health, 2001a: p. 24). This reflects a radical change in the way that adverse events or ‘near misses' in medicine are to be investigated. Drawing on lessons from engineering on improving safety in aviation and the nuclear power industry, the Department of Health has moved from an individual to a system-centred approach. Whereas the traditional investigation generally stopped when human error was identified, the systems approach takes error as a symptom, not a cause, and asks why it happened, and what were the factors operating on the individual that contributed to the negative outcome (Department of Health, 2000). This approach to investigations could potentially lead to far more constructive solutions than those offered by the current system of inquiries after homicides.
Fluoxetine therapy in depersonalisation disorder: Randomised controlled trial
Authors: Simeon Daphne , Guralnik Orna , Schmeidler James , Knutelska Margaret
Published: June 2004

Background

Despite anecdotal reports that serotonin reuptake inhibitors may improve depersonalisation, there is no proven efficacious treatment for depersonalisation disorder.

Aims

To investigate the efficacy of fluoxetine in the treatment of depersonalisation disorder.

Method

Fifty-four people who met DSM-IV criteria for depersonalisation disorder were recruited through newspaper advertisements, and 50 were randomised to a 10-week, double-blind trial of fluoxetine 10–60 mg/day or placebo. Primary outcome measures were the Dissociative Experiences Scale-epersonalisation Factor, the Depersonalization Severity Scale and the Clinical Global Impression-Improvement (CGI-1) scale.

Results

Intention-to-treat analysis revealed that fluoxetine (mean dosage 48 mg/day) was not superior to placebo except for a clinically minimal but statistically significantly greater improvement in CGI-I score in the fluoxetine group prior to covarying for anxiety and depression (2.9 v. 3.6). Depersonalisation was significantly more likely to improve if comorbid anxiety disorder improved.

Conclusions

Fluoxetine was not efficacious in treating depersonalisation disorder, despite the commonly reported clinical use of serotonin reuptake inhibitors for this condition.
Psychotherapy alone and combined with pharmacotherapy in the treatment of depression
Authors: De Jonghe Frans , Hendricksen Mariëlle , Van Aalst Gerda , Kool Simone , Peen Vjaap , Van Rien , Van Den Eijnden Ellen , Dekker Jack
Published: June 2004

Background

The relative efficacy of psychotherapy and combined therapy in the treatment of depression is still a matter of debate.

Aims

To investigate whether combined therapy has advantages over psychotherapy alone.

Method

A 6-month randomised clinical trial compared Short Psychodynamic Supportive Psychotherapy (n= 106) with combined therapy (n=85) in ambulatory patients with mild or moderate major depressive disorder diagnosed using DSM-IV criteria. Antidepressants were prescribed according to a protocol providing four successive steps in case of intolerance or inefficacy: venlafaxine, selective serotonin reuptake inhibitor, nortriptyline and nortriptyline plus lithium. Efficacy was assessed using the 17-item Hamilton Rating Scale for Depression, the Clinical Global Impression of Severity and of Improvement, and the depression sub-scale of the Symptom Checklist.

Results

The advantages of combining antidepressants with psychotherapy were equivocal. Neither the treating clinicians nor the independent observers were able to ascertain them, but the patients experienced them clearly.

Conclusions

The advantages of combining antidepressants with psychotherapy are equivocal.
Pituitary volume in psychosis
Authors: Pariante Carmine M. , Vassilopoulou Konstantina , Velakoulis Dennis , Phillips Lisa , Soulsby Bridget , Wood Stephen J. , Brewer Warrick , Smith Deidrej. , Dazzan Paola , Yung Alison R. , Zervas Ioannis M. , Christodoulou George N. , Murray Robin , McGorry Patrick D. , Pantelis Christos
Published: June 2004

Background

Patients with psychosis have activation of the hypothalamic-pituitary-adrenal (HPA) axis during the acute phase of the psychosis. Whether this has any morphological consequences for the pituitary gland is currently unknown.

Aims

To examine pituitary volume variation in people at different stages of psychotic disorder.

Method

Pituitary volume was measured using 1.5 mm, coronal magnetic resonance images in 24 people with first-episode psychosis, 51 with established schizophrenia and 59 healthy controls.

Results

Compared with the control group, the people with first-episode psychosis had pituitary volumes that were 10% larger, whereas those with established schizophrenia had pituitary volumes that were 17% smaller. In both of the groups with psychosis, there was no difference in pituitary volume between those receiving typical antipsychotic drugs and those receiving atypical antipsychotics.

Conclusions

The first episode of a psychosis is associated with a larger pituitary volume, which we suggest is due to activation of the HPA axis. The smaller pituitary volume in the group with established schizophrenia could be the consequence of repeated episodes of HPA axis hyperactivity.
Cost-effectiveness of computerised cognitive-behavioural therapy for anxiety and depression in primary care: Randomised controlled trial
Authors: McCrone Paul , Knapp Martin , Proudfoot Judith , Ryden Clash , Cavanagh Kate , Shapiro David A. , Ilson Sophie , Gray Jeffrey A. , Goldberg David , Mann Anthony , Marks Isaac , Everitt Brian , Tylee Andre
Published: June 2004

Background

Cognitive-behavioural therapy (CBT) is effective for treating anxiety and depression in primary care, but there is a shortage of therapists. Computer-delivered treatment may be a viable alternative.

Aims

To assess the cost-effectiveness of computer-delivered CBT.

Method

A sample of people with depression or anxiety were randomised to usual care (n= 128) or computer-delivered CBT (n= 146). Costs were available for 123 and 138 participants, respectively. Costs and depression scores were combined using the net benefit approach.

Results

Service costs were £40 (90% CI-£28 to £148) higher over 8 months for computer-delivered CBT. Lost-employment costs were £407 (90% CI £196 to £586) less for this group. Valuing a 1-unit improvement on the Beck Depression Inventory at £40, there is an 81% chance that computer-delivered CBT is cost-effective, and it revealed a highly competitive cost per quality-adjusted life year.

Conclusions

Computer-delivered CBT has a high probability of being cost-effective, even if a modest value is placed on unit improvements in depression.
Rapid tranquillisation of violent or agitated patients in a psychiatric emergency setting
Authors: Alexander Jacob , Tharyan Prathap , Adams Clive , John Thomas , Mol Carina , Philip Joncy
Published: June 2004

Background

The pharmacological management of violence in people with psychiatric disorders is under-researched.

Aims

To compare interventions commonly used for controlling agitation or violence in people with serious psychiatric disorders.

Method

We randomised 200 people to receive intramuscular lorazepam (4 mg) or intramuscular haloperidol (10 mg) plus promethazine (25–50 mg mix).

Results

At blinded assessments 4 h later (99.5% follow-up), equal numbers in both groups (96%) were tranquil or asleep. However, 76% given the haloperidol-promethazine mix were asleep compared with 45% of those allocated lorazepam (RR=2.29, 95% CI 1.59–3.39; NNT=3.2, 95% CI 2.3–5.4). The haloperidol-promethazine mix produced a faster onset of tranquillisation/sedation and more clinical improvement over the first 2 h. Neither intervention differed significantly in the need for additional intervention or physical restraints, numbers absconding, or adverse effects.

Conclusions

Both interventions are effective for controlling violent/agitated behaviour. If speed of sedation is required, the haloperidol-promethazine combination has advantages over lorazepam.
Focus on psychiatry in Singapore
Authors: Kua Ee Heok
Published: June 2004

This is an overview of the historical development of psychiatric services and the progress of psychiatric research and training in Singapore. With a population of 4 million, the city is evolving from developing to developed status and the concomitant social implications pose enormous challenges for mental health professionals. The demographic changes in recent years, with an ageing population and with more women (the traditional family caregivers) in the workforce, have had profound consequences for the delivery of health care services. In this cosmopolitan city of Chinese, Indians and Malays, myriad cultures and beliefs influence the health-seeking behaviour and the care of people with mental illness.
Commission for Health Improvement and mental health Services
Authors: Oyebode Femi , Berrisford Giles , Parry Liz
Published: June 2004

The Commission for Health Improvement (CHI) ceased to function at the end of March 2004. This provides the opportunity to review its contribution and achievements as a new body, the Commission for Healthcare Audit and Inspection (CHAI), takes over its functions∗. CHI recently published its assessment of mental health services (http://www.chi.nhs.uk/eng/news/2003/dec/11.shtml). The report is based on the 35 clinical governance reviews, in England and Wales, published between July 2001 and October 2003; two investigations into serious service failures; and a report on safeguarding arrangements for children in England and a self-audit of child protection arrangements. CHI concluded that mental health services lag behind acute health services in developing clinical governance systems and processes that promote high-quality care and continuous improvement. It specifically highlighted the shortages of psychiatrists and in-patient nurses, and the reliance on agency nurses and locum staff; the unsuitability of buildings and facilities; the pressures on in-patient beds; the lack of management capacity and poor information systems; and the low priority given to services for children and older people.
Evaluation of a partial hospitalisation programme: good news and bad
Authors: Tacchi Mary Jane , Joseph Suresh , Scott Jan
Published: June 2004

Aims and Method

To evaluate a 50-place partial hospitalisation programme during its first year of operation. Data were recorded for consecutive referrals to the programme. Its effects on the admission unit were also assessed.

Results

The unit received over 200 referrals over 12 months, and more than 60% were for individuals who might otherwise have been admitted. The programme was associated with reductions in number and duration of hospital admissions and in bed occupancy rate; however, the proportion of urgent referrals to the programme doubled over the year, and after 12 months the occupancy rate was 96%.

Clinical Implications

The programme was well received by clients and well used by clinicians. Although it initially reduced the pressure on in-patient services, the problems confronting the programme at the end of the evaluation mirrored those of in-patient units.
Multiple domains control the subcellular localization and activity of ETR-3, a regulator of nuclear and cytoplasmic RNA processing events
Authors: Ladd Andrea N. , Cooper Thomas A.
Published: June 2004

Embryonic lethal abnormal vision (ELAV) type RNA binding protein 3 (ETR-3; also called NAPOR, CUGBP2, or BRUNOL3) has been implicated in the regulation of nuclear and cytoplasmic RNA processing events, including alternative splicing, RNA editing, stability and translation. Here, we report that the ETR-3 protein contains multiple regions that control its subcellular localization and are important for its activity as a splicing regulator. We cloned ETR-3 from chicken heart and fused it to the C terminus of green fluorescent protein (GFPcETR3vL). GFPcETR3vL is found predominantly in the nucleus and is an active regulator of alternative splicing in cotransfection assays with a cardiac troponin T minigene. ETR-3 contains two N-terminal RNA recognition motifs (RRMs), a 210-amino acid divergent domain, and a C-terminal RRM. We demonstrate that the C terminus contains a strong nuclear localization signal overlapping the third RRM, which can confer nuclear localization on a normally cytoplasmic pyruvate kinase chimera. Additional deletions revealed nuclear localization and export activities in the divergent domain of ETR-3, as well as regions within the first two RRMs that are important for cytoplasmic localization. The nuclear export activity of the divergent domain is sensitive to leptomycin B, indicating that export to the cytoplasm is mediated via a CRM1-dependent pathway. The C terminus and a region within the divergent domain were also shown to be important for splicing activity of ETR-3. This is the first characterization of protein domains involved in mediating the subcellular localization and splicing activity of a member of the CELF family of RNA processing regulators.
Disruption of Rho signal transduction upon cell detachment
Authors: Ren Xiang-Dong , Wang Ruixue , Li Qinyuan , Kahek Lobna A. F. , Kaibuchi Kozo , Clark Richard A. F.
Published: June 2004

Serum-soluble factors play a dominant role in the activation of the small GTPase RhoA. Cell adhesion also modulates RhoA activity but the effect is modest in the absence of serum. Here, we show that cell adhesion is required for serum-stimulated Rho signal transduction leading to myosin light chain (MLC) phosphorylation. Characterization of Rho-kinase substrates revealed that diphosphorylation of MLC at Thr-18 and Ser-19 (ppMLCT18/S19) and phosphorylation of the myosin-binding subunit (MBS) of myosin phosphatase at Thr-853 (pMBST853) were mostly Rho and Rho-kinase dependent in attached fibroblasts. MLC monophosphorylation at Ser-19 (pMLCS19) was partially dependent on Rho kinase, whereas phosphorylation of MBS at Thr-696 (pMBST696) and phosphorylation of CPI-17 at Thr-38 (pCPI-17T38) were mostly Rho-kinase independent. Cell detachment caused a significant reduction in pMLCS19 and a more dramatic decrease of ppMLCT18/S19 without inhibiting RhoA. pMBST853, pMBST696 and pCPI-17T38 were not significantly reduced, suggesting that myosin-phosphatase activity was little changed. Cells expressing active RhoA (RhoAV14) or Rho-kinase catalytic domain maintained elevated pMBST853 upon detachment but failed to support ppMLCT18/S19, indicating that the ability of Rho kinase to phosphorylate MLC is impaired. Reattachment to immobilized fibronectin resulted in a gradual recovery of Rho-kinase-induced ppMLCT18/S19 that is absent from the cells attached to poly-L-lysine. The convergence of signals from soluble factors and cell adhesion might therefore occur at the point of MLC phosphorylation, providing an effective mechanism for dynamic control of contractility during cell migration.
Under stress, the absence of intermediate filaments from Müller cells in the retina has structural and functional consequences
Authors: Lundkvist Andrea , Reichenbach Andreas , Betsholtz Christer , Carmeliet Peter , Wolburg Hartwig , Pekny Milos
Published: June 2004

In epithelial and muscle cells, intermediate filaments (IFs) are important for resistance to mechanical stress. The aim of this study was to elucidate whether IFs are also important for providing resistance to mechanical stress in the Müller cells of the retina and whether this has any pathophysiological consequences. We used mice deficient in IF proteins glial fibrillary acidic protein and/or vimentin (GFAP–/–, Vim–/– and GFAP–/–Vim–/–), and stress on the retina was applied by excision of the eyes immediately post mortem (compared with in situ fixation) or by inducing a neovascular response to oxygen-induced retinopathy (OIR). The structure of unchallenged retinas was normal, but mechanical stress caused local separation of the inner limiting membrane (ILM) and adjacent tissue from the rest of the retina in GFAP–/–Vim–/– mice and, to a lesser extent, in Vim–/– mice. This detachment occurred within the endfeet of Müller cells, structures normally rich in IFs but IF-free in GFAP–/–Vim–/– mice. Hypoxia-induced neovascularization was comparable in all groups of mice with respect to the retinal surface area occupied by new vessels. However, the vessels traversed the ILM and penetrated the vitreous body less frequently than in wild-type retinas (31-55% in Vim–/–, 66-79% in GFAP–/–Vim–/–). We conclude that IFs are important for maintaining the mechanical integrity of Müller-cell endfeet and the inner retinal layers under a mechanical challenge. Furthermore, the absence of IFs in Müller cells leads to an abnormal response of the vascular system to ischemia, specifically decreased ability of newly formed blood vessels to traverse the ILM.
Spatial and temporal control of mitotic cyclins by the Gnu regulator of embryonic mitosis inDrosophila
Authors: Zhang Xiao-Hua , Axton J. Myles , Drinjákovic Jována , Lorenz Lena , White-Cooper Helen , Renault Andrew D.
Published: June 2004

Mutation of the Drosophila maternal cell cycle regulator, Gnu, results in loss of embryonic mitosis and the onset of excessive nuclear DNA replication. The Gnu phosphoprotein is normally synthesized in nurse cells and transported to the developing oocyte. We created a gnuGFP-bcd3′UTR transgene using the gnu promoter and bicoid 3′UTR, that translates GnuGFP only on egg activation from a localized anterior source. This transgene was able to rescue the sterility of gnu mutant females. Gnu is therefore first required after egg activation for polar body condensation and zygotic mitoses. Embryos containing pronounced anterior-posterior gradients of Gnu activity demonstrate that Gnu regulates mitotic activity by promoting cyclin B stability. Our gnuGFP-bcd3′UTR vector provides a novel experimental strategy to analyse the temporal requirement and role of cell cycle regulators including potential sperm-supplied factors in eggs and embryos.
Drug Use Patterns in Young German Women and Association with Mental Disorders
Authors: Hach Isabel , Rentsch Anke , Ruhl Uwe E , Becker Eni S , Türke Veneta , Margraf Jürgen , Kirch Wilhelm
Published: June 2004

BACKGROUND:

There is a lack of data about drug use patterns in young women. Mental disorders may influence those drug use patterns.

OBJECTIVE:

To evaluate drug use patterns (prescribed drugs, self-medication) in general and in relation to the prevalence rates of mental disorders in young German women.

METHODS:

A total of 2064 women (18–24 y old), obtained in a random clustered sample, were asked about their actual and former medication use. Moreover, a structured psychological interview (Diagnostic Interview for Mental Disorders) was conducted with each woman to evaluate the prevalence of mental disorders (according to the Diagnostic and Statistical Manual of Mental Disorders, 4th edition).

RESULTS:

Oral contraceptives (55.9%), thyroid preparations (7.1%), respiratory system drugs (9.4%), and nervous system drugs (8%) were the most commonly used medications. Only 10% of the women with one or more mental disorders used psychotropic medication. As expected, women with mental disorders were significantly more likely to use antidepressants and psycholeptic agents (ie, sedatives/hypnotics, antipsychotics) than were women without any mental disorder. However, there were no significant differences in use of pain medication.

CONCLUSIONS:

The results of this study indicate an apparently inadequate supply of drugs acting on the nervous system for women with mental disorders in Germany. Further studies on different age and gender groups are needed. It is important to evaluate the prevalence of diseases and drug use at the same time so as to identify deficits in drug therapy and optimize prescription and self-medication use.
Sustained Extracellular Signal-Regulated Kinase 1/2 Phosphorylation in Neonate 6-Hydroxydopamine-Lesioned Rats after Repeated D1-Dopamine Receptor Agonist Administration: Implications for NMDA Receptor Involvement
Authors: Papadeas Sophia T. , Blake Bonita L. , Knapp Darin J. , Breese George R.
Published: June 2004

Extracellular signal-regulated kinase (ERK) 1/2, a well known regulator of gene expression, is likely to contribute to signaling events underlying enduring neural adaptations. Phosphorylated (phospho)-ERK was examined immunohistochemically after both single and repeated (i.e., sensitizing) doses of the partial D1-dopamine (DA) receptor agonist SKF-38393 (2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benazepine HCl) to adult rats lesioned as neonates (neonate lesioned) with 6-hydroxydopamine. Remarkably, prolonged phospho-ERK accumulated primarily in layers II-III of medial prefrontal cortex (MPC), where it declined gradually yet remained significantly elevated for at least 36 d after repeated doses of SKF-38393. Sustained (≥7 d) phospho-ERK was observed for shorter periods in various other cortical regions but was not detectable in striatum or nucleus accumbens. At 36 d, an additional injection of SKF-38393 to sensitized rats restored phospho-ERK to maximal levels only in MPC when examined 7 d later. Phosphorylated cAMP response element-binding protein (CREB), examined 7 d after the sensitizing regimen, was observed exclusively in MPC, where it was abundant throughout all layers. Systemic injections of SL327 (α-[amino[(4-aminophenyl)thio]methylene]-2-(trifluoromethyl)benzeneacetonitrile), an inhibitor of the upstream ERK activator mitogen ERK kinase, attenuated both ERK and CREB phosphorylation in layers II-III of MPC. Pretreatment with the D1antagonist SCH-23390 ((R)-(+)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepine-7-OL maleate) inhibited the prolonged increase in MPC phospho-ERK, whereas the 5-HT2receptor antagonist ketanserin (3-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl]-2,4(1H,3H)-quinazolinedione tartrate) was ineffective. Competitive and noncompetitive NMDA receptor antagonists also blocked sustained ERK phosphorylation. Collectively, the present results demonstrate coupling of D1and NMDA receptor function reflected in sustained activation of the ERK signaling pathway in MPC of SKF-38393-sensitized neonate-lesioned rats. Ultimately, long-lasting phosphorylation of ERK and CREB in MPC may play a pivotal role in any permanent adaptive change(s) in these animals.
Structural Abnormalities in the Brains of Human Subjects Who Use Methamphetamine
Authors: Thompson Paul M. , Hayashi Kiralee M. , Simon Sara L. , Geaga Jennifer A. , Hong Michael S. , Sui Yihong , Lee Jessica Y. , Toga Arthur W. , Ling Walter , London Edythe D.
Published: June 2004

We visualize, for the first time, the profile of structural deficits in the human brain associated with chronic methamphetamine (MA) abuse. Studies of human subjects who have used MA chronically have revealed deficits in dopaminergic and serotonergic systems and cerebral metabolic abnormalities. Using magnetic resonance imaging (MRI) and new computational brain-mapping techniques, we determined the pattern of structural brain alterations associated with chronic MA abuse in human subjects and related these deficits to cognitive impairment. We used high-resolution MRI and surface-based computational image analyses to map regional abnormalities in the cortex, hippocampus, white matter, and ventricles in 22 human subjects who used MA and 21 age-matched, healthy controls. Cortical maps revealed severe gray-matter deficits in the cingulate, limbic, and paralimbic cortices of MA abusers (averaging 11.3% below control;p< 0.05). On average, MA abusers had 7.8% smaller hippocampal volumes than control subjects (p< 0.01; left,p= 0.01; right,p< 0.05) and significant white-matter hypertrophy (7.0%;p< 0.01). Hippocampal deficits were mapped and correlated with memory performance on a word-recall test (p< 0.05). MRI-based maps suggest that chronic methamphetamine abuse causes a selective pattern of cerebral deterioration that contributes to impaired memory performance. MA may selectively damage the medial temporal lobe and, consistent with metabolic studies, the cingulate-limbic cortex, inducing neuroadaptation, neuropil reduction, or cell death. Prominent white-matter hypertrophy may result from altered myelination and adaptive glial changes, including gliosis secondary to neuronal damage. These brain substrates may help account for the symptoms of MA abuse, providing therapeutic targets for drug-induced brain injury.
Retroinhibition of Presynaptic Ca2+Currents by Endocannabinoids Released via Postsynaptic mGluR Activation at a Calyx Synapse
Authors: Kushmerick Christopher , Price Gareth D. , Taschenberger Holger , Puente Nagore , Renden Robert , Wadiche Jacques I. , Duvoisin Robert M. , Grandes Pedro , von Gersdorff Henrique
Published: June 2004

We investigated the mechanisms by which activation of group I metabotropic glutamate receptors (mGluRs) and CB1 cannabinoid receptors (CB1Rs) leads to inhibition of synaptic currents at the calyx of Held synapse in the medial nucleus of the trapezoid body (MNTB) of the rat auditory brainstem. In ∼50% of the MNTB neurons tested, activation of group I mGluRs by the specific agonist (s)-3,5-dihydroxyphenylglycine (DHPG) reversibly inhibited AMPA receptor- and NMDA receptor-mediated EPSCs to a similar extent and reduced paired-pulse depression, suggestive of an inhibition of glutamate release. Presynaptic voltage-clamp experiments revealed a reversible reduction of Ca2+currents by DHPG, with no significant modification of the presynaptic action potential waveform. Likewise, in ∼50% of the tested cells, the CB1 receptor agonist (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone (WIN) reversibly inhibited EPSCs, presynaptic Ca2+currents, and exocytosis. For a given cell, the amount of inhibition by DHPG correlated with that by WIN. Moreover, the inhibitory action of DHPG was blocked by the CB1R antagonistN-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (AM251) and occluded by WIN, indicating that DHPG and WIN operate via a common pathway. The inhibition of EPSCs by DHPG, but not by WIN, was abolished after dialyzing 40 mmBAPTA into the postsynaptic cell, suggesting that DHPG activated postsynaptic mGluRs. Light and electron microscopy immunolabeling indicated a presynaptic expression of CB1Rs and postsynaptic localization of mGluR1a. Our data suggest that activation of postsynaptic mGluRs triggers the Ca2+-dependent release of endocannabinoids that activate CB1 receptors on the calyx terminal, which leads to a reduction of presynaptic Ca2+current and glutamate release.
Gene Expression Changes in the Course of Neural Progenitor Cell Differentiation
Authors: Gurok Ulf , Steinhoff Christine , Lipkowitz Bettina , Ropers H.-Hilger , Scharff Constance , Nuber Ulrike A.
Published: June 2004

The molecular changes underlying neural progenitor differentiation are essentially unknown. We applied cDNA microarrays with 13,627 clones to measure dynamic gene expression changes during thein vitrodifferentiation of neural progenitor cells that were isolated from the subventricular zone of postnatal day 7 mice and grownin vitroas neurospheres. In two experimental series in which we withdrew epidermal growth factor and added the neurotrophins Neurotrophin-4 or BDNF, four time points were investigated: undifferentiated cells grown as neurospheres, and cells 24, 48, and 96 hr after differentiation. Expression changes of selected genes were confirmed by semiquantitative RT-PCR. Ten different groups of gene expression dynamics obtained by cluster analysis are described. To correlate selected gene expression changes to the localization of respective proteins, we performed immunostainings of cultured neurospheres and of brain sections from adult mice. Our results provide new insights into the genetic program of neural progenitor differentiation and give strong hints to as yet unknown cellular communications within the adult subventricular zone stem cell niche.
GABA Uptake via GABA Transporter-1 Modulates GABAergic Transmission in the Immature Hippocampus
Authors: Sipilä Sampsa , Huttu Kristiina , Voipio Juha , Kaila Kai
Published: June 2004

GABA uptake limits GABA actions during synaptic responses when the density of active release sites is high or multiple axons are synchronously activated. GABA transporter-1 (GAT-1) is the main neuronal GABA transporter subtype and is already expressed in the early postnatal rat hippocampus. However, previous studies have demonstrated little functional role for the transporter during this developmental period. We used whole-cell voltage-clamp and field-potential recordings in hippocampal slices of neonatal rats (postnatal day 4-5) to study whether GAT-1 plays a role in GABAergic transmission during spontaneous population oscillations, which are seen as “giant depolarizing potentials” (GDPs) in intracellular recordings. We show that the GDP-associated GABAergic current observed in CA3 pyramidal neurons is strongly enhanced by the GAT-1-specific blocker NO-711 (1-[2-[[(diphenylmethylene)imino]oxy]ethyl]-1,2,5,6-tetrahydro-3-pyridinecarboxylic acid hydrochloride). Our results indicate a novel role for GAT-1 in the control of endogenous activity of the immature hippocampus.
Induction of Dickkopf-1, a Negative Modulator of the Wnt Pathway, Is Associated with Neuronal Degeneration in Alzheimer's Brain
Authors: Caricasole Andrea , Copani Agata , Caraci Filippo , Aronica Eleonora , Rozemuller Annemieke J. , Caruso Alessandra , Storto Marianna , Gaviraghi Giovanni , Terstappen Georg C. , Nicoletti Ferdinando
Published: June 2004

We used primary cultures of cortical neurons to examine the relationship between β-amyloid toxicity and hyperphosphorylation of the tau protein, the biochemical substrate for neurofibrillary tangles of Alzheimer's brain. Exposure of the cultures to β-amyloid peptide (βAP) induced the expression of the secreted glycoprotein Dickkopf-1 (DKK1). DKK1 negatively modulates the canonical Wnt signaling pathway, thus activating the tau-phosphorylating enzyme glycogen synthase kinase-3β. DKK1 was induced at late times after βAP exposure, and its expression was dependent on the tumor suppressing protein p53. The antisense induced knock-down of DKK1 attenuated neuronal apoptosis but nearly abolished the increase in tau phosphorylation in βAP-treated neurons. DKK1 was also expressed by degenerating neurons in the brain from Alzheimer's patients, where it colocalized with neurofibrillary tangles and distrophic neurites. We conclude that induction of DKK1 contributes to the pathological cascade triggered by β-amyloid and is critically involved in the process of tau phosphorylation.
Whisker Vibration Information Carried by Rat Barrel Cortex Neurons
Authors: Arabzadeh Ehsan , Panzeri Stefano , Diamond Mathew E.
Published: June 2004

Rats can make extremely fine texture discriminations by “whisking” their vibrissa across the surface of an object. We have investigated one hypothesis for the neuronal basis of texture representation by measuring how clusters of neurons in the barrel cortex of anesthetized rats encode the kinetic features of sinusoidal whisker vibrations. Mutual information analyses of spike counts led to a number of findings. Information about vibration kinetics became available as early as 6 msec after stimulus onset and reached a peak at ∼20-30 msec. Vibration speed, proportional to the product of vibration amplitude (A) and frequency (f), was the kinetic property most reliably reported by cortical neurons. Indeed, by measuring information when the complete stimulus set was collapsed into feature-defined groups, we found that neurons reduced the dimensionality of the stimulus from two features (A, f) to a single feature, the productAf. Moreover, because different neurons encode stimuli in the same manner, information loss was negligible even when the activity of separate neuronal clusters was pooled. This suggests a decoding scheme whereby target neurons could capture all available information simply by summating the signals from separate barrel cortex neurons. These results indicate that neuronal population activity provides sufficient information to allow nearly perfect discrimination of two vibrations, based on their deflection speeds, within a time scale comparable with that of a single whisking motion across a surface.
Distribution and Speciation of Metals in Surface Sediments of Taranto Gulf (Ionian Sea, Southern Italy)
Authors: Buccolieri Alessandro , Buccolieri Giovanni , Cardellicchio Nicola , DELL'ATTI Angelo , Di Leo Antonella , Maci Antonella , Petronio Bianca Maria
Published: June 2004

Concentrations of metals (Al, Fe, Ti, Ni, Mn, Cr, Zn, Cu, Pb) were determined in surface sediments from Taranto gulf (Ionian Sea, Southern Italy) in order to assess the distribution and the bioavailability of metals. Total metal content and speciation of Fe, Ni, Mn, Zn, Cu and Pb were determined. Sediment cores were also sampled in some stations of particular interest. The analytical results show that metals distribution does not show significant variations in relation to depth. Metal distribution in the Taranto gulf is mainly influenced by industrial wastes from Taranto town, by rivers of the Basilicata region and by prevailing anticlockwise marine currents. These factors cause an accumulation of metals in the sediments near to the coasts of Calabria. The statistical analysis, effected by HCA and PCA methods, can be considered a good starting point in order to classify sediment samples and to locate accumulation areas. Metal speciation shows that Fe, Ni and Zn are present in sediments mainly as sulphides, Mn is present principally in an ionexchange form or bound to carbonate, while Cu and Pb are mainly present in the fraction bounds to humic acids.
The Role of Organic Matter on Metal Toxicity and Bio‐Availability
Authors: Calace Nicoletta , Petronio Bianca Maria
Published: June 2004

A short review concerning the role of organic matter on metal toxicity and bio‐availability in aqueous systems is carried out. The complexity of the issue derives both from the high number of natural and anthropogenic organic compounds and from the variability of their structures. In fact, the binding capacity and affinity is dependent on the number and type of ligands, on their position in the structures, on the ligand/metal ratio. It is also necessary to develop analytical protocol in order to carry out speciation studies of organic carbon and of metals bound to organic compounds, and at the same time to characterise the nature of the complexes.
Bioavailability, Bioaccumulation and Tolerance of Chromium: Consequences in the Food Chain of Freshwater Ecosystems
Authors: Gorbi Gessica , Invidia Marion , Zanni Corrado , Torelli Anna , Corradi Maria Grazia
Published: June 2004

Many abiotic and biotic factors can influence the partitioning equilibrium of heavy metals, thus influencing metal impact on aquatic environments. Unicellular algal species release soluble organic substances able to complex metals. In our laboratory a Cr‐tolerant strain was selected and isolated from a wild type strain of Scenedesmus acutus. The exudates released by the two strains counteracted the growth inhibition caused by Cr(VI) and the exudates of the Cr‐tolerant strain were more effective. On the contrary, the exudates did not reduce chromium toxicity to the cladoceran Daphnia magna. The reduction of chromium effect on algae seems the consequence of an algae‐specific interaction among Cr(VI), exudates and algal cells. Chromium uptake resulted to be energy‐dependent since bioaccumulation rate in subdued light condition was lower than at high light intensity. The effect of Cr(VI) on algae changed depending on metabolism of the cells and in particular it seemed to be related to the bioaccumulation rate. Tolerance in the selected strain could not be ascribed to a lower uptake of chromium. The difference in sensitivity to chromium between the two strains was exploited to evaluate if tolerance acquired by algae could have consequences for Daphnia. After treatment with Cr(VI), the two strains of S. acutus were used as food source for D. magna. The results indicate that chromium is accumulated by algae in a form not available for daphnids and that Cr tolerance acquired by the algae can be of some advantage to the consumer organism.