bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phosphorylation of HIV Tat by PKR increases interaction with TAR RNA and enhances transcription
Authors: Endo-Munoz Liliana , Warby Tammra , Harrich David , McMillan Nigel A J 
Published: March 2005

Abstract
Background
The interferon (IFN)-induced, dsRNA-dependent serine/threonine protein kinase, PKR, plays a key regulatory role in the IFN-mediated anti-viral response by blocking translation in the infected cell by phosphorylating the alpha subunit of elongation factor 2 (eIF2). The human immunodeficiency virus type 1 (HIV-1) evades the anti-viral IFN response through the binding of one of its major transcriptional regulatory proteins, Tat, to PKR. HIV-1 Tat acts as a substrate homologue for the enzyme, competing with eIF2α, and inhibiting the translational block. It has been shown that during the interaction with PKR, Tat becomes phosphorylated at three residues: serine 62, threonine 64 and serine 68. We have investigated the effect of this phosphorylation on the function of Tat in viral transcription. HIV-1 Tat activates transcription elongation by first binding to TAR RNA, a stem-loop structure found at the 5' end of all viral transcripts. Our results showed faster, greater and stronger binding of Tat to TAR RNA after phosphorylation by PKR.

Results
We have investigated the effect of phosphorylation on Tat-mediated transactivation. Our results showed faster, greater and stronger binding of Tat to TAR RNA after phosphorylation by PKR. In vitro phosphorylation experiments with a series of bacterial expression constructs carrying the wild-type tat gene or mutants of the gene with alanine substitutions at one, two, or all three of the serine/threonine PKR phosphorylation sites, showed that these were subject to different levels of phosphorylation by PKR and displayed distinct kinetic behaviour. These results also suggested a cooperative role for the phosphorylation of S68 in conjunction with S62 and T64. We examined the effect of phosphorylation on Tat-mediated transactivation of the HIV-1 LTR in vivo with a series of analogous mammalian expression constructs. Co-transfection experiments showed a gradual reduction in transactivation as the number of mutated phosphorylation sites increased, and a 4-fold decrease in LTR transactivation with the Tat triple mutant that could not be phosphorylated by PKR. Furthermore, the transfection data also suggested that the presence of S68 is necessary for optimal Tat-mediated transactivation.

Conclusion
These results support the hypothesis that phosphorylation of Tat may be important for its function in HIV-1 LTR transactivation.
Reduced hippocampal volumes and memory loss in patients with early- and late-onset depression
Authors: Hickie Ian , Naismith Sharon , Ward Philip B. , Turner Keelin , Scott Elizabeth , Mitchell Philip , Wilhelm Kay , Parker Gordon 
Published: March 2005

BackgroundHippocampal volume reduction has been reported inconsistently in people with major depression.AimsTo evaluate the interrelationships between hippocampal volumes, memory and key clinical, vascular and genetic risk factors.MethodTotals of 66 people with depression and 20 control participants underwent magnetic resonance imaging and clinical assessment. Measures of depression severity, psychomotor retardation, verbal and visual memory and vascular and specific genetic risk factors were collected.ResultsReduced hippocampal volumes occurred in older people with depression, those with both early-onset and late-onset disorders and those with the melancholic subtype. Reduced hippocampal volumes were associated with deficits in visual and verbal memory performance.ConclusionsAlthough reduced hippocampal volumes are most pronounced in late-onset depression, older people with early-onset disorders also display volume changes and memory loss. No clear vascular or genetic risk factors explain these findings. Hippocampal volume changes may explain how depression emerges as a risk factor to dementia.
Hypofrontality in men with first-episode psychosis
Authors: Molina V. , Sanz J. , Reig S. , Martínez R. , Sarramea F. , Luque R. , Benito C. , Gispert J. D. , Pascau J. , Desco M. 
Published: March 2005

BackgroundDecreased metabolic activity in the prefrontal cortex during cognitive activation is a recurrent finding and a likely functional marker of schizophrenia.AimsTo investigate the occurrence of hypofrontality in patients with first-episode psychosis, with or without evolution to schizophrenia.MethodWe used fluorodeoxyglucose positron emission tomography during the performance of an attention task and magnetic resonance imaging to study the dorsolateral prefrontal region in 13 men with a first episode of psychosis. Data from patients who progressed to schizophrenia were compared with those of patients who did not meet criteria for this diagnosis after 2 years.ResultsPatients who developed schizophrenia demonstrated a significant hypofrontality in the dorsolateral prefrontal cortex in comparison with the non-schizophrenia and control groups.ConclusionsOur results suggest that hypofrontality could be a marker of schizophrenia at the time of the first psychotic episode, in agreement with neurodevelopmental theories of schizophrenia.
Nicotine dependence and symptoms in schizophrenia
Authors: Aguilar M. Carmen , Gurpegui Manuel , Diaz Francisco J. , De Leon Jose 
Published: March 2005

BackgroundSmoking may have a beneficial effect on either schizophrenic symptoms or antipsychotic side-effects, but studies are hampered by the lack of control of confounding factors.AimsTo explore the self-medication hypothesis in a large sample of stable out-patients with schizophrenia.MethodSymptoms, assessed with the Positive and Negative Syndrome Scale (PANSS), and number of hospitalisations were compared in 250 out-patients with DSM–IV schizophrenia classified into three categories: highly dependent smokers, mildly dependent smokers and non-smokers. Log-linear analysis was used to control for potential confounding and interacting variables.ResultsHigh PANSS total scores and positive symptoms were less frequent in mildly dependent smokers than in non-smokers or highly dependent smokers. The highly dependent smokers had the worst outcome.ConclusionsThe data do not generally support the self-medication hypothesis but rather suggest a complex interaction between nicotine dependence and schizophrenic symptoms.
Escitalopram in the treatment of social anxiety disorder
Authors: Kasper Siegfried , Stein Dan J. , Loft Henrik , Nil Rico 
Published: March 2005

BackgroundSelective serotonin reuptake inhibitors are effective in the treatment of social anxiety disorder and are currently regarded as the pharmacotherapy of choice.AimsTo investigate the efficacy and tolerability of escitalopram in the treatment of generalised social anxiety disorder.MethodPatients with generalised social anxiety disorder were randomised to receive placebo (n=177) or 10–20 mg escitalopram (n=181) in a 12-week, double-blind trial. The primary outcome measure was the mean change from baseline to last assessment in the Liebowitz Social Anxiety Scale (LSAS) total score.ResultsThe study showed a statistically superior therapeutic effect for escitalopram compared with placebo on the LSAS total score (P=0.005). There were significantly more responders to treatment for escitalopram than for placebo (54% v. 39%; P < 0.0 1). The clinical relevance of these findings was supported by significant reduction in the work and social components of the Sheehan Disability Scale and by the good tolerability of escitalopram treatment.ConclusionsEscitalopram was efficacious and well tolerated in the treatment of generalised social anxiety disorder.
Assessing adolescent personality pathology
Authors: Westen Drew , Dutra Lissa , Shedler Jonathan 
Published: March 2005

BackgroundPersonality pathology constitutes a major form of psychopathology in adolescents.AimsTo examine the reliability and validity of a Q-sort instrument for assessing adolescent personality pathology designed for clinically experienced informants.MethodA sample of 294 randomly selected psychiatrists and psychologists each provided data on a current patient, aged 14–18 years. Clinicians completed several measures, including the Shedler–Westen Assessment Procedure for Adolescents (SWAP–200–A).ResultsFactor analysis identified II dimensions of adolescent personality: psychopathology/malignant narcissism, dysphoria/inhibition, psychological health, histrionic sexualisation, schizotypy, sexual conflict, emotional dysregulation, anxious obsessionality, peer rejection, delinquent behaviour and attentional dysregulation. These correlated in predicted ways with a range of criterion variables, including measures of adaptive functioning, Axis II pathology, the Five Factor Model and the Child Behavior Checklist.ConclusionsThe SWAP–200–A shows promise as an instrument for assessing personality pathology in adolescents. Trait dimensions such as delinquent behaviour and emotional dysregulation may prove useful additions to a classification of personality.
Suitability and utility of the CORE–OM and CORE–A for assessing severity of presenting problems in psychological therapy services based in primary and secondary care settings
Authors: Barkham Michael , Gilbert Naomi , Connell Janice , Marshall Chris , Twigg Elspeth 
Published: March 2005

BackgroundThere is a need for reliable assessment tools that are suitable for the counselling and the psychological therapy services in primary and secondary care settings.AimsTo test the suitability and utility of the Clinical Outcomes in Routine Evaluation – Outcome Measure (CORE–OM) and CORE–Assessment (CORE–A) assessment tools.MethodService intake data were analysed from counselling and psychological therapy services in 32 primary care settings and 17 secondary care settings.ResultsCompletion rates exceeded 98% in both of the settings sampled. Intake severity levels were similar but secondary care patients were more likely to score above the risk cut-off and the severe threshold and to have experienced their problems for a greater duration.ConclusionsThe CORE–OM and CORE–A are suitable assessment tools that show small but logical differences between psychological therapy services in primary- and secondary-based care.
Psychiatric advance directives: qualitative study of informed deliberations by mental health service users
Authors: Amering Michaela , Stastny Peter , Hopper Kim 
Published: March 2005

BackgroundEstablished legal mandates and high expectations for psychiatric advance directives are not matched by empirical evidence documenting their actual implementation.AimsTo explore the interests, concerns and planning activities of informed mental health service users contemplating such directives.MethodStandard qualitative research techniques were used: field observations, interviews, focus groups, archival research and key informant interviews; 33 persons participated in the interviews and focus groups. Transcripts were coded and analysed for thematic content, and results were member-checked.ResultsTraining set in motion labour-intensive projects: conceptualising how a psychiatric advance directive would work in one's life, mobilising resources, reviewing past experiences and assessing risks. Especially meaningful was the prospect of being treated as a responsible agent in future interactions with the mental health system.ConclusionsAdvance directives are best thought of as complex planning tools for future psychiatric crisis management, rather than focal interventions to enhance compliance. Research is needed to explore the institutional response to this prospective decision-sharing initiative.
Risk of puerperal and non-puerperal recurrence of illness following bipolar affective puerperal (post-partum) psychosis
Authors: Robertson Emma , Jones Ian , Haque Sayeed , Holder Roger , Craddock Nick 
Published: March 2005

SummaryThe clinical value of information on the risk of future psychiatric illness in women who have experienced puerperal (post-partum) psychosis has been limited by inconsistencies in terminology and nosology. Here we report rates of subsequent puerperal and non-puerperal episodes, in a well-characterised sample of women diagnosed with clearly defined bipolar affective puerperal psychosis (n=103). Out of 54 women having further children, 31 (57%; 95% Cl 44–69) experienced an additional puerperal psychotic episode, and 64 of 103 women (62%; 95%Cl 52–71) experienced a non-puerperal affective episode during the follow-up period (mean duration 9 years). A history of bipolar episodes prior to the puerperal psychosis did not predict risk following subsequent pregnancies, but positive family history of mental illness predicted shorter time to non-puerperal relapse.
Establishing a dose–response relationship for haloperidol decanoate
Authors: Taylor David 
Published: March 2005

Aims and MethodThe aim of this literature analysis was to establish the range of doses of haloperidol decanoate effective in preventing relapse in schizophrenia. Studies reporting relapse rates in patients treated for longer than 6 months were included. Relapse rate was then plotted against dose or log dose to allow drawing of dose–response curves.ResultsFifteen publications reporting 13 individual studies were identified. of these, 6 studies met inclusion criteria and were analysed. Dose–response curves indicated limited effect at 25 mg/4 weeks but near maximal effect at doses of 50 mg/4 weeks. There was no clear evidence that increasing the dose above 100 mg/4 weeks provided additional benefit in preventing relapse.Clinical ImplicationsThe recommended dose range for haloperidol decanoate (50–300 mg/ 4 weeks) does not reflect the findings of this study. Optimally effective doses appear to be around 50–100 mg/4 weeks. The use of doses above 100 mg/4 weeks is difficult to support given data available.
Parenteral thiamine use in the prevention and treatment of Wernicke–Korsakoff syndrome
Authors: McIntosh Claire , Kippen Valerie , Hutcheson Fiona , McIntosh Andrew 
Published: March 2005

Aims and MethodA pre-/post-intervention audit of 163 case notes was conducted to assess the efficacy of printing information about the identification and treatment of the Wernicke–Korsakoff syndrome on the hospital alcohol detoxification sheet.ResultsParenteral thiamine was indicated in 42 of 163 patients; 26 had symptoms suggestive of Wernicke's encephalopathy and 16 were at risk. The intervention increased the chance of appropriate parenteral treatment by an odds ratio of 5.9 (95% CI 1.3–27.8). Admission to a specialist alcohol unit increased the chance of appropriate treatment by an odds ratio of 7.0 (95% CI 1.52–32.25). The mean number of doses rose from 3.08 to 4.62.Clinical ImplicationsA simple intervention may lead to improved treatment of patients with Wernicke–Korsakoff syndrome.
How safe is lithium prescribing? Audit of a local prescribing framework and patient survey
Authors: Glover Katherine J. , Lawley David 
Published: March 2005

Aims and MethodTo examine the standards of lithium monitoring in eastern Hull following the introduction of a local prescribing framework, we investigated the biochemistry records of patients currently prescribed lithium, identified from primary care computerised records. A survey of patients' knowledge about lithium therapy was also conducted.ResultsInadequate standards of lithium monitoring were demonstrated, with only 50% of patients having a level recorded during the preceding 3 months. Monitoring of thyroid and renal function was better, with two-thirds of patients tested in the past year. Patients' knowledge of the side-effects and risks of lithium was minimal; only 7 out of 27 patients questioned felt able to identify the signs of lithium toxicity; three-quarters of those surveyed felt they had not been given enough information about their medication.Clinical ImplicationsThe introduction of prescribing frameworks or other guidelines does not ensure good practice. Further actions may be needed to ensure lithium is prescribed safely, such as patient registers, monitoring cards and automatic recall systems. Education of patients and primary care staff about the safe use of psychotropic drugs needs to be an ongoing process.
Mutations of the Epidermal Growth Factor Receptor Gene Predict Prolonged Survival After Gefitinib Treatment in Patients With Non–Small-Cell Lung Cancer With Postoperative Recurrence
Authors: Mitsudomi Tetsuya , Kosaka Takayuki , Endoh Hideki , Horio Yoshitsugu , Hida Toyoaki , Mori Shoichi , Hatooka Shunzo , Shinoda Masayuki , Takahashi Takashi , Yatabe Yasushi 
Published: March 2005

Purpose To evaluate the relationship between mutations of the epidermal growth factor receptor (EGFR) gene and the effectiveness of gefitinib treatment in patients with recurrent lung cancer after pulmonary resection. Patients and Methods We sequenced exons 18-21 of the EGFR gene using total RNA extracted from 59 patients with lung cancer who were treated with gefitinib for recurrent lung cancer. Gefitinib effectiveness was evaluated by both imaging studies and change in serum carcinoembryonic antigen (CEA) levels. Results EGFR mutations were found in 33 patients (56%). Of these mutations, 17 were deletions around codons 746-750 and 15 were point mutations (12 at codon 858, three at other codons), and one was an insertion. EGFR mutations were significantly more prevalent in females, adenocarcinoma, and never-smokers. Gefitinib treatment resulted in tumor shrinkage and/or CEA decrease to less than half of the baseline level in 26 patients, tumor growth and/or CEA elevation in 24 patients, and gefitinib effect was not assessable in nine patients. Female, never-smoking patients with adenocarcinoma tended to respond better to gefitinib treatment. Gefitinib was effective in 24 of 29 patients with EGFR mutations, compared with two of 21 patients without mutations (P < .0001). Of note, del746-750 might be superior to L858R mutations for prediction of gefitinib response. Patients with EGFR mutations survived for a longer period than those without the mutations after initiation of gefitinib treatment (P = .0053). Conclusion EGFR mutations were a good predictor of clinical benefit of gefitinib in this setting.
The Metabolic Syndrome and Disturbances in Hormone Levels in Long-Term Survivors of Disseminated Testicular Cancer
Authors: Nuver Janine , Smit Andries J. , Wolffenbuttel Bruce H.R. , Sluiter Wim J. , Hoekstra Harald J. , Sleijfer Dirk T. , Gietema Jourik A. 
Published: March 2005

Purpose The metabolic syndrome may be an important risk factor for cardiovascular disease in long-term survivors of testicular cancer (TC). We investigated the associations between hormone levels and the metabolic syndrome in these men. Patients and Methods We included TC patients cured by orchidectomy and cisplatin-based chemotherapy, stage I TC patients after orchidectomy only, and healthy men of comparable age. Presence of the metabolic syndrome was determined using guidelines from the National Cholesterol Education Program Adult Treatment Panel III. Thyroid-stimulating hormone, follicle-stimulating hormone (FSH), inhibin B, luteinizing hormone (LH), total testosterone, sex-hormone–binding globulin, free testosterone, estradiol, dehydroepiandrosterone sulfate, and insulin-like growth factor 1 were determined in blood. Cortisol metabolite excretion was measured in urine. Results Eighty-six chemotherapy patients (median follow-up, 7 years) were compared with 44 stage I patients and 47 controls. LH and FSH were higher, and inhibin B and total and free testosterone were lower in chemotherapy patients than controls. Adrenal and thyroid hormone production were unaffected. Chemotherapy patients with the metabolic syndrome (n = 22; 26%) had a higher body mass index (BMI) pretreatment, a larger BMI increase during follow-up, lower total testosterone, and higher urinary cortisol metabolite excretion than those patients without the metabolic syndrome. BMI and insulin were associated with the metabolic syndrome, while total testosterone and urinary cortisol metabolite excretion were associated with BMI. Conclusion We found gonadal dysfunction, but normal adrenal and thyroid function. Through its association with BMI, testosterone may play a role in the development of the metabolic syndrome in long-term TC survivors.
Eradication of Minimal Residual Disease in B-Cell Chronic Lymphocytic Leukemia After Alemtuzumab Therapy Is Associated With Prolonged Survival
Authors: Moreton Paul , Kennedy Ben , Lucas Guy , Leach Michael , Rassam Saad M.B. , Haynes Andrew , Tighe Jane , Oscier David , Fegan Christopher , Rawstron Andy , Hillmen Peter 
Published: March 2005

Purpose To test whether eradication of minimal residual disease (MRD) in B-cell chronic lymphocytic leukemia (CLL) by alemtuzumab is associated with a prolongation of treatment-free and overall survival. Patients and Methods Ninety-one previously treated patients with CLL (74 men and 17 women; median age, 58 years [range, 32 to 75 years]; 44 were refractory to purine analogs) received a median of 9 weeks of alemtuzumab treatment between 1996 and 2003. Regular bone marrow assessments by MRD flow cytometry were performed with the aim of eradicating detectable MRD (< 1 CLL cell in 105 normal cells). Results Responses according to National Cancer Institute-sponsored working group response criteria were complete remission (CR) in 32 patients (36%), partial remission (PR) in 17 patients (19%), and no response (NR) in 42 patients (46%). Twenty-two (50%) of 44 purine analog-refractory patients responded to alemtuzumab. Detectable CLL was eradicated from the blood and marrow in 18 patients (20%). Median survival was significantly longer in MRD-negative patients compared with those achieving an MRD-positive CR, PR, or NR. Patients achieving an MRD-negative CR had a longer treatment-free survival than patients with MRD-positive CRs, PR, or NR: MRD-negative CRs, not reached; MRD-positive CRs, 20 months; PRs, 13 months; NR, 6 months (P < .0001). Overall survival for the 18 patients with MRD-negative remissions was 84% at 60 months. Eight (47%) of the MRD-negative patients converted to MRD positivity at a median of 28 months. Conclusion MRD-negative remission in CLL is achievable with alemtuzumab, leading to an improved overall and treatment-free survival.