bluuebunny/crossref_metadata_2025 huggingface dataset:
New component of the limbic system: Marginal division of the neostriatum that links the limbic system to the basal nucleus of Meynert
Authors: Shu Si Yun , Bao Xin Min , Ning Qun , Wu Yong Ming , Wang Jun , Leonard Brian E.
Published: February 2003

The limbic system refers to a group of connected neural regions that are associated with motivation, learning, and memory. The marginal division (MrD) is a zone located at the caudal border of the neostriatum in mammalian brains that has been shown to be involved in learning and memory. In a previous study, c‐fos expression showed functional connections between the MrD, basal nucleus of Meynert (NBM) and limbic system (Shu et al., 1988a, 1999). In the present study, to explore the relationship between these regions, the expression of limbic system‐associated membrane protein (LAMP) was investigated using molecular and immunohistochemical methods. Synaptic and functional connections between the MrD and the NBM were studied also using tract tracing, electron microscopic and behavioral methods. LAMP is thought to be a marker of the limbic system and expression of LAMP protein and mRNA was observed in both the MrD and the limbic system. From such results, it is concluded that the MrD is a new component of the limbic system. Fibers from the MrD were observed projecting and synapsing on cholinergic neurons of the NBM. As reduction of learning and memory was induced by lesioning the projection from the MrD to the NBM, it would seem that the MrD modulates the learning and memory function of the NBM. In conclusion, the results of these studies suggest that the MrD is a new component of the limbic system, and there are functional and structural connections between the MrD, NBM and limbic system. The MrD seems to act as a link between the limbic system and the NBM, and plays a role in learning and memory. © 2002 Wiley‐Liss, Inc.
Pyrrolidine dithiocarbamate‐induced neuronal cell death is mediated by Akt, casein kinase 2, c‐Jun N‐terminal kinase, and IκB kinase in embryonic hippocampal progenitor cells
Authors: Min Young Kyu , Park Jae Hyun , Chong Seon Ah , Kim Yun Sook , Ahn Young Soo , Seo Jeong Taeg , Bae Young Suk , Chung Kwang Chul
Published: February 2003

Pyrrolidine dithiocarbamate (PDTC) is known to induce cell death by the stimulation of intracellular zinc transport and subsequent modulation of nuclear factor‐κB (NF‐κB) activity. Zinc is a signaling messenger that is released by neuronal activity at many central excitatory synapses. Excessive synaptic release of zinc followed by entry into vulnerable neurons contributes to severe neuronal cell death. In the present study, we explored how PDTC modulates intracellular signal transduction pathways, leading to neuronal cell death. The exposure of immortalized embryonic hippocampal cells (H19‐7) to PDTC within the range of 1–100 μM caused cell death in a dose‐dependent manner. During the cell death, NF‐κB activity increased in response to PDTC, and this activity corresponded well with the increase of intracellular free zinc levels, implying that the activation of NF‐κB transmits the cell death signals of PDTC. Furthermore, PDTC caused the activation of IκB kinase (IKK), casein kinase 2 (CK2), phosphatidylinositol 3‐kinase (PI‐3K), and Akt, as well as mitogen‐activated protein kinases (MAPKs), such as extracellular signal‐regulated kinase (ERK) and c‐Jun N‐terminal kinase (JNK), but not p38 kinase. The blockade of PI‐3K, JNK, and CK2 pathways resulted in a remarkable suppression of PDTC‐induced cell death and also the activation of IKK, which subsequently led to a decrease of IκB phosphorylation. Although the overexpression of dominant‐negative SEK in a transient manner did not inhibit the activation of Akt by PDTC, the transfection of kinase‐inactive Akt mutants did cause a remarkable blockade of JNK activation, implying that Akt is present upstream of JNK in the PDTC‐signaling pathways. Moreover, whereas selective CK2 inhibitors suppressed PDTC‐induced JNK activation, the inhibition of JNK did not affect CK2 activity, suggesting that CK2 is directly related to the regulation of cell viability by PDTC and that the CK2‐JNK pathway could be a downstream target of PDTC. Taken together, our results suggest that PDTC‐mediated accumulation of intracellular zinc ions may affect cell viability by modulating several intracellular signaling pathways in neuronal hippocampal progenitor cells. © 2002 Wiley‐Liss, Inc.
Ein Sterilisationsprozess kann die Eigenschaften von Biokeramik verändern
Authors: Willmann G.
Published: February 2003

Biokeramik auf Basis von bioinertem Aluminium‐ und Zirkonoxid, so wie bioaktivem Hydroxylapatit sind etablierte Werkstoffe für Implantate. Implantate müssen gereinigt und sterilisiert werden. Bei einigen Biokeramiken können beim Sterilisieren Veränderungen ihrer Farbe auftreten, die aber keinen ungünstigen Einfluß auf die Gebrauchseigenschaften haben. Das Sterilisieren mit Dampf im Autoklaven und mit Co60 Gamma Strahlung verursacht keinen Festigkeitsabfall bei Aluminiumoxidkeramik und bei dem neuen, keramischen Biokomposit AMC (Alumina Matrix Composite).

Bei Y‐TZP Zirkonoxidkeramik dagegen wurde beim Sterilisieren mit Dampf ein Festigkeitsabfall gefunden.
Spinally generated electromyographic oscillations and spasms in a low‐thoracic complete paraplegic
Authors: Norton Jonathan A. , Wood Duncan E. , Marsden Jonathan F. , Day Brian L.
Published: February 2003

We have measured some oscillatory properties of severe lower limb spasms experienced by a low‐thoracic complete paraplegic during assisted standing. Electromyograms (EMG) were recorded from the leg muscles while the patient stood passively in a standing frame. The patient also stood using functional electrical stimulation (FES) while ground and handle reaction force vectors were measured together with EMG activity. During passive standing, spasms appeared simultaneously in all leg muscle groups on one side. The interval between spasms varied between 3 and 30 seconds. Within the spasms, there was a tendency of repetitive grouped discharge of motor units as well as a strong 10‐Hz component in the EMG that was coherent across ipsilateral muscle groups. Thus, the spasms were inherently oscillatory. During FES‐assisted standing, clinically similar spasms were observed. However, the interspasm interval became relatively fixed at around 16 seconds, which may indicate entraining of the spasm cycle by FES. There are similarities between this patient's spasms and the pathological motor activities seen in other movement disorders that may also be of spinal origin.
Secondary cervical dystonia associated with structural lesions of the central nervous system
Authors: LeDoux Mark S. , Brady Kimberly A.
Published: February 2003

We tested the hypothesis that structural lesions of the central nervous system (CNS) associated with cervical dystonia more commonly involve the cerebellum and its primary afferent pathways than basal ganglia structures. Cervical dystonia is the most common focal dystonia, the majority of cases are idiopathic, and only a small percentage of patients have a family history of dystonia or other movement disorders. Pathophysiological mechanisms operative in solely or predominantly appendicular dystonias such as writer's cramp and Oppenheim's dystonia, respectively, may not be directly applicable to axial dystonias. The localization of structural lesions of the CNS associated with secondary cervical dystonia may provide some insight into the neural structures potentially involved in primary cervical dystonia. The National Library of Medicine Gateway (from 1960) and a clinical database maintained by the senior author (from 1999) were searched for cases of secondary cervical dystonia associated with structural lesions of the CNS. Search terms included one or more of the following: dystonia, torticollis, cervical, secondary, and symptomatic. Lesion localization and type, patient age, patient gender, head position, occurrence of sensory tricks, and associated neurological findings were tabulated for each case. Structural lesions associated with cervical dystonia were most commonly localized to the brainstem and cerebellum. The remaining cases were equally divided between the cervical spinal cord and basal ganglia. Although inconsistent, head rotation tended to be contralateral to lesion localization. Additional neurological abnormalities were present in the majority of patients with secondary cervical dystonia. The relative paucity of basal ganglia pathology and concentration of lesions in the brainstem, cerebellum, and cervical spinal cord in patients with secondary cervical dystonia suggests that dysfunction of cerebellar afferent pathways may be important to the pathophysiology of primary cervical dystonia. © 2002 Movement Disorder Society
Pelvic movements as rhythmic motor manifestation associated with restless legs syndrome
Authors: Lombardi Carolina , Provini Federica , Vetrugno Roberto , Plazzi Giuseppe , Lugaresi Elio , Montagna Pasquale
Published: February 2003

Video‐polysomnographic monitoring of a patient with a 4‐year history of an unpleasant restless sensation originating in his lower abdomen showed stereotyped, repetitive, rhythmic pelvic body movements resembling coital behaviour at the wake–sleep transition. We discuss the association between restless legs syndrome and rhythmic movement disorder as a particular manifestation of a spectrum of rhythmic sleep‐related movement disorders.
Systematic review of incidence studies of Parkinson's disease
Authors: Twelves Dominique , Perkins Kate S.M. , Counsell Carl
Published: February 2003

Incidence studies of Parkinson's disease (PD) are important for both health‐care planning and epidemiological research. This report reviews the methods and results of previous incidence studies of PD and makes recommendations for future studies. Original articles that described the incidence of PD were located using several strategies. The methods were summarised, and the results of studies with similar methodologies were compared on a standardised population. Twenty‐five incidence studies were included. Each used different methods to identify incident patients, although most screened both primary care and hospital records. Only eight studies were prospective, and only two of these had any follow‐up. The diagnostic criteria for PD varied (11 studies used two or more cardinal motor features, four used the UK Brain Bank criteria), as did the exclusion criteria and the definition of an incident case. In 16 studies, attempts were made to confirm the diagnosis by examination of patients by a specialist as part of the study. None of the studies used identical methods, but five were sufficiently similar to merit comparison. Four of these gave a similar incidence (16–19/100,000/year), but one from Italy had a much lower incidence (8.4/100,000), the reason for which was unclear. Five studies found significantly greater incidence in men. This review highlights the difficulties in performing good quality incidence studies of PD. Further incidence studies using standardised methods are required. A set of minimal scientific criteria has been devised to improve the quality and consistency of future studies.
Automatic assessment of levodopa‐induced dyskinesias in daily life by neural networks
Authors: Keijsers Noël L.W. , Horstink Martin W.I.M. , Gielen Stan C.A.M.
Published: February 2003

We developed an objective and automatic procedure to assess the severity of levodopa‐induced dyskinesia (LID) in patients with Parkinson's disease during daily life activities. Thirteen patients were continuously monitored in a home‐like situation for a period of approximately 2.5 hours. During this time period, the patients performed approximately 35 functional daily life activities. Behavior of the patients was measured using triaxial accelerometers, which were placed at six different positions on the body. A neural network was trained to assess the severity of LID using various variables of the accelerometer signals. Neural network scores were compared with the assessment by physicians, who evaluated the continuously videotaped behavior of the patients off‐line. The neural network correctly classified dyskinesia or the absence of dyskinesia in 15‐minute intervals in 93.7, 99.7, and 97.0% for the arm, trunk, and leg, respectively. In the few cases of misclassification, the rating by the neural network was in the class next to that indicated by the physicians using the AIMS score (scale 0–4). Analysis of the neural networks revealed several new variables, which are relevant for assessing the severity of LID. The results indicate that the neural network can accurately assess the severity of LID and could distinguish LID from voluntary movements in daily life situations. © 2002 Movement Disorder Society
Experimental parkinsonism is associated with increased pallidal GAD gene expression and is reversed by site‐directed antisense gene therapy
Authors: Schneider Jay S. , Wade Timothy V.
Published: February 2003

The levels of mRNA encoding the two isoforms of glutamic acid decarboxylase (GAD65 and GAD67) were measured throughout the pallidal complex in normal and acutely (i.e., 1 month duration) and chronically (i.e., 5 years duration) parkinsonian 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine hydrochloride (MPTP) ‐treated monkeys as well as in monkeys exposed to MPTP but asymptomatic for parkinsonism. GAD65 mRNA labeling was modestly increased in the mid/caudal internal globus pallidus (GPi) but not in the external globus pallidus (GPe) in parkinsonian monkeys, compared with normal and asymptomatic monkeys. GAD67 mRNA expression was highly increased in the mid/caudal GPi, and modestly increased in the GPe in parkinsonian monkeys compared with normal and asymptomatic animals. Infusion of GAD67 antisense oligodeoxynucleotides bilaterally into the GPi resulted in a transient reversal of akinesia and bradykinesia that was not produced by infusion of missense oligodeoxynucleotides. These data emphasize the role of GAD enzyme (particularly GAD67) and GABA in the GPi for the expression of parkinsonian motor signs and suggest that selective manipulation of GABAergic neurotransmission in the GPi may have therapeutic potential for treating parkinsonism. © 2002 Movement Disorder Society
Putting people first: How VSP achieves high employee satisfaction year after year
Authors: Leuchars Elaine , Harrington Shauna , Erickson Carrie
Published: February 2003

VSP is the nation's largest provider of eyecare benefits, with nearly 37 million members in its
plan—more than any other healthcare organization in the country. Over the past decade, VSP has seen its
workforce nearly triple, from 868 to 2,100 employees. During the same period, the company engaged in a
multi‐pronged effort to preserve and even improve its close‐knit culture and high employee
engagement. The result has been a sustained period of high employee satisfaction with VSP as a place to work.

VSP's HR department recently stepped back to assess the results of its own efforts since its inception in
1992 and, in particular, to identify those programs it considered to be most successful in nurturing the high
levels of employee satisfaction that the company enjoys. We report here on our major areas of focus and a number of
the satisfaction‐enhancing employee programs that have helped put VSP on Fortune's
list of the “100 Best Companies to Work For” for the last three years. © 2003 Wiley
Periodicals, Inc.
Effects of cyazofamid against Plasmodiophora brassicae Woronin on Chinese cabbage
Authors: Mitani Shigeru , Sugimoto Koji , Hayashi Hiroyuki , Takii Yasuko , Ohshima Takeshi , Matsuo Norifusa
Published: February 2003

Cyazofamid (4‐chloro‐2‐cyano‐N,N‐dimethyl‐5‐p‐tolylimidazole‐1‐sulfonamide) is a novel fungicide with high levels of activity against Oomycetes fungi and Plasmodiophora brassicae Woronin. The effects of cyazofamid were investigated against P brassicae, the causal agent of clubroot disease in Chinese cabbage. Cyazofamid at 0.3 mg litre−1 inhibited resting spore germination of this pathogen by about 80%. Cyazofamid at 3–10 mg litre−1 exhibited fungicidal activity to resting spores of P brassicae 1–10 days after treatment. When cyazofamid was applied to infested soil, both root‐hair infections and club formation caused by P brassicae were strongly inhibited at 1–3 mg kg−1 dry soil. These results suggest that cyazofamid directly inhibits resting spore germination, thereby leading to the inhibition of root‐hair infection and club formation. Cyazofamid at 3 mg kg−1 dry soil also exhibited complete control of clubroot disease. The effect of broadcast soil application using a dust formulation at 2 kg AI ha−1 (equivalent to 1.3 mg AI kg−1 dry soil), and plug seedling tray application by a suspension concentrate formulation at 200 and 400 mg AI tray−1 (30 × 60 × 4 cm3) against P brassicae was also evaluated. Cyazofamid exhibited good efficacy against the pathogen. The sequential treatment including plug seedling tray application with cyazofamid and pre‐plant broadcast soil application with the fungicide fluazinam also exhibited excellent levels of control. These results indicate that cyazofamid has a high potential to be an effective fungicide for the control of clubroot disease.

© 2003 Society of Chemical Industry
Monitoring of atrazine treatment on soil bacterial, fungal and atrazine‐degrading communities by quantitative competitive PCR
Authors: Martin‐Laurent Fabrice , Piutti Séverine , Hallet Stéphanie , Wagschal Isabelle , Philippot Laurent , Catroux Gérard , Soulas Guy
Published: February 2003

We report the development of quantitative competitive (QC) PCR assays for quantifying the 16S, 18S ribosomal and atzC genes in nucleic acids directly extracted from soil. QC‐PCR assays were standardised, calibrated and evaluated with an experimental study aiming to evaluate the impact of atrazine application on soil microflora. Comparison of QC‐PCR 16S and 18S results with those of soil microbial biomass showed that, following atrazine application, the microbial biomass was not affected and that the amount of 16S rDNA gene representing ‘bacteria’ increased transitorily, while the amount of 18S rDNA gene representing fungi decreased in soil. In addition, comparison of atzC QC‐PCR results with those of atrazine mineralisation revealed that, in response to atrazine treatment, the amount of atzC gene increased transitorily in soil pre‐treated with atrazine, suggesting that accelerated atrazine biodegradation in soil could be due to a transient increase in the size of the atrazine mineralising community.

© 2003 Society of Chemical Industry
Learning performances of honeybees (Apis mellifera L) are differentially affected by imidacloprid according to the season
Authors: Decourtye Axel , Lacassie Eric , Pham‐Delègue Minh‐Hà
Published: February 2003

To establish the sublethal concentrations domain, acute and chronic oral tests were conducted on caged honeybee workers (Apis mellifera L) using imidacloprid and a metabolite, 5‐OH‐imidacloprid, under laboratory conditions. The latter showed a 48‐h oral LD50 value (153 ng per bee) five times higher than that of imidacloprid (30 ng per bee). Chronic feeding tests indicated that the lowest observed effect concentrations (LOEC) of imidacloprid and of 5‐OH‐imidacloprid on mortality of winter bees were 24 and 120 µg kg−1 respectively. Behavioural effects of imidacloprid and 5‐OH‐imidacloprid were studied using the olfactory conditioning of proboscis extension response at two periods of the year. Winter bees surviving chronic treatment with imidacloprid and 5‐OH‐imidacloprid had reduced learning performances. The LOEC of imidacloprid was lower in summer bees (12 µg kg−1) than in winter bees (48 µg kg−1), which points to a greater sensitivity of honeybees behaviour in summer bees, compared to winter bees.

© 2003 Society of Chemical Industry
Impact of alternative respiration and target‐site mutations on responses of germinating conidia of Magnaporthe grisea to Qo‐inhibiting fungicides
Authors: Avila‐Adame Cruz , Köller Wolfram
Published: February 2003

Qo‐inhibiting fungicides act as respiration inhibitors by binding to the Qo center of cytochrome b. Sensitivities of fungi to Qo inhibitors can be influenced by the induction of alternative respiration or by mutational changes of the cytochrome b target site. Previous studies on both mechanisms in Magnaporthe grisea (Hebert) Barr were focused on the mycelial stage of the pathogen. The present study describes the expression and impact of both resistance mechanisms during the stage of conidia germination. In the absence of a host, alternative respiration provided a >500‐fold rescue from azoxystrobin during the germination of conidia derived from four wild‐type isolates of M grisea. This rescue potential during conidia gemination was substantially more pronounced than for mycelial growth. However, the pronounced effectiveness of alternative respiration during conidia germination was not apparent when barley leaves were protected with azoxystrobin prior to inoculation with conidia. In a comparison of a wild‐type strain and an alternative respiration‐deficient mutant, azoxystrobin efficacies in suppressing symptom development differed by a factor of two, with full disease control achieved for both genotypes at 1 µg ml−1 azoxystrobin. In contrast, conidia derived from two QoI‐resistant target site mutants were highly resistant to azoxystrobin and trifloxystrobin and fully capable of infecting leaf surfaces protected with 10 µg ml−1 of azoxystrobin. Both target‐site mutants had emerged spontaneously in the presence of high azoxystrobin doses when residual mycelial growth was supported by alternative respiration. The effective silencing of alternative respiration in protective applications of Qo‐inhibiting fungicides might constitute a strategy of slowing the emergence of highly resistant target site mutants.

© 2003 Society of Chemical Industry
Relative effects of the insecticide thiamethoxam on the predator Podisus nigrispinus and the tobacco whitefly Bemisia tabaci in nectaried and nectariless cotton
Authors: Torres Jorge B , Silva‐Torres Christian S A , Barros Reginaldo
Published: February 2003

The predaceous stinkbug Podisus nigrispinus (Dallas) (Heteroptera: Pentatomidae) feeds on plants as well as on arthropod prey. The question arises whether feeding on plants might expose the predator to systemic insecticide via ingestion of the active ingredient or its metabolites through plant sap of treated plants. This interaction was investigated with nectaried and nectariless cotton plants cropped in pots and treated with the systemic insecticide thiamethoxam at 0.5, 1.0 and 2.0 mg per plant as a root drench. Development of P nigrispinus fed on prey and on treated nectaried and nectariless cotton plants and confined at 15, 30 and 45 days after insecticide application, and adult reproduction from nymphs caged 30 days after treatment were determined. Podisus nigrispinus life history traits were unaffected by the type of cotton plant, nectaried or nectariless, but were significantly affected by insecticide dose and time after application. Developmental time was extended and fresh adult body weight was reduced by feeding on prey and treated plants. Nymphs caged on treated plants with the highest thiamethoxam concentration at 15 days after application produced only 13.2% of adults. Females emerged from nymphs caged on both plants and at all thiamethoxam concentrations at day 30 after application presented similar reproductive characteristics, except for age of first oviposition, which was delayed on plants treated with the highest thiamethoxam concentration. Thiamethoxam at 0.5 mg per plant restrained tobacco whitefly, Bemisia tabaci Gennadius (Homoptera: Aleyrodidae) colonization only during the first 15 days after application to either cotton plant, and similar immature densities were sampled at day 35 after application on treated and untreated plants. However, plants treated with 1.0 and 2.0 mg per plant as a drench and cropped in pots were protected from tobacco whitefly for up to 45 days after exposure to a whitefly colony.

© 2003 Society of Chemical Industry
A laboratory evaluation of the palatability of legumes to the field slug,Deroceras reticulatumMüller
Authors: Brooks Andrew S , Crook Mitchell J , Wilcox Andrew , Cook Richard T
Published: February 2003

Slugs are major pests of many crops, including winter wheat, in temperate climates, yet current methods of control are often unreliable. The aim of this study is to investigate the potential for common legume species to act as an alternative source of food, or trap crop, for the most damaging agricultural pest species, the grey field slug,Deroceras reticulatumMüller, thereby reducing damage to the wheat crop. A series of three controlled‐environment experiments were designed to assess this aim. Individual slugs were fed leaves of one of ten legume species together with winter wheat leaves for a 72‐h period. A clear hierarchy of acceptability was shown, with red clover, lucerne, lupin and white clover showing significantly higher Acceptability Indices than the other six species tested. Red clover produced the greatest reduction in mean wheat consumption (78%) from day 1 to day 3. When species were fed individually, red clover was consumed in significantly greater quantities than any of the other treatments: 40% more than white clover and 56% more than wheat. Furthermore, when fed with red clover the amount of wheat consumed was some 50% less than when the latter was fed alone. The results indicate that legumes vary greatly in their acceptability toD reticulatumand it is essential that a legume with a high Acceptability Index is chosen, which results in the least amount of wheat consumed.

© 2003 Society of Chemical Industry
Therapeutic equivalence: fallacies and falsification
Authors: Garrett Andrew D.
Published: February 2003

The number of studies designed specifically to demonstrate therapeutic equivalence or alternatively non‐inferiority of pharmaceutical treatments has increased dramatically in recent years, during which time awareness of the methodological issues has increased. Regulatory authorities have been quick to recognize the need for specific support and have either published or initiated the creation of relevant guidance. Common misconceptions prevail however regarding sample size estimation and the choice of the most appropriate patient population to analyse while other areas such as equivalence margin specification and covariate adjustment have been neglected. This paper challenges some of the regulatory advice and the interpretation that others have made of this guidance with the aim of stimulating further debate. Copyright © 2003 John Wiley & Sons, Ltd.
Sequential designs for phase III clinical trials incorporating treatment selection
Authors: Stallard Nigel , Todd Susan
Published: February 2003

Most statistical methodology for phase III clinical trials focuses on the comparison of a single experimental treatment with a control. An increasing desire to reduce the time before regulatory approval of a new drug is sought has led to development of two‐stage or sequential designs for trials that combine the definitive analysis associated with phase III with the treatment selection element of a phase II study. In this paper we consider a trial in which the most promising of a number of experimental treatments is selected at the first interim analysis. This considerably reduces the computational load associated with the construction of stopping boundaries compared to the approach proposed by Follman, Proschan and Geller (Biometrics 1994; 50: 325–336). The computational requirement does not exceed that for the sequential comparison of a single experimental treatment with a control. Existing methods are extended in two ways. First, the use of the efficient score as a test statistic makes the analysis of binary, normal or failure‐time data, as well as adjustment for covariates or stratification straightforward. Second, the question of trial power is also considered, enabling the determination of sample size required to give specified power. Copyright © 2003 John Wiley & Sons, Ltd.
Comparison of stratification and adaptive methods for treatment allocation in an acute stroke clinical trial
Authors: Weir Christopher J. , Lees Kennedy R.
Published: February 2003

Achieving balance on prognostic factors between treatment groups in a clinical trial is important to ensure that any observed treatment effect may be attributed to the treatment itself. Improving the balance on prognostic factors also potentially increases the statistical power attained in a trial. Substantial imbalances may occur by chance if simple randomization is used. Allocation of the treatment according to stratified random blocks based on clinical features is the conventional approach to obtain treatment groups that are as similar as possible. An alternative approach, known as minimization (or more generally as adaptive stratification), has also been proposed. We assessed the feasibility of adaptive stratification in the context of a clinical trial of insulin to control plasma glucose level following acute stroke. We determined suitable settings for the parameters in the adaptive stratification procedure by simulation studies. Specifically, we assessed: the optimal probability for allocating a patient to the preferred (leading to least imbalance on prognostic factors) treatment group; the number of variables that could be incorporated in the adaptive stratification algorithm; the weighting that should be given to each variable; and whether interactions between variables should be included. We then compared the statistical power, across a range of simulated treatment effects, between trials where treatments were allocated by stratified random blocks and by adaptive stratification. Finally, we considered the importance of the method of analysis in realizing the gain in power which may potentially be achieved by allocating treatments using stratified random blocks or adaptive stratification. Copyright © 2003 John Wiley & Sons, Ltd.
Sensitivity analysis for the estimation of rates of change with non‐ignorable drop‐out: an application to a randomized clinical trial of the vitamin D3
Authors: Matsuyama Yutaka
Published: February 2003

The vitamin D3trial was a repeated measures randomized clinical trial for secondary hyperparathyroidism in haemodialysis patients where the efficacy of the vitamin D3infusions for suppressing the secretion of parathyroid hormone (PTH) was compared among four dose groups over 12 weeks. In this trial, patients terminated the study before the scheduled end of the study due to their elevated serum calcium (Ca) level, that is, the administration of the vitamin D3was expected to cause hypercalcaemia as an adverse event. In this setting of monotone missingness, there is a potential for bias in estimation of mean rates of decline in PTH for each treatment group using the standard methods such as the generalized estimating equations (GEE) which ignore the observed past Ca histories. We estimated the treatment‐group‐specific mean rates of decline in PTH by the inverse probability of censoring weighted (IPCW) methods which account for the observed past histories of time‐dependent factors that are both a predictor of drop‐out and are correlated with the outcomes. The IPCW estimator can be viewed as an extension of the GEE estimator that allows for the data to be MAR but not MCAR. With missing data, it is rarely appropriate to analyse the data solely under the assumption that the missing data process is ignorable, because the assumption of ignorable missingness cannot be guaranteed to hold and is untestable from the observed data. We proposed a sensitivity analysis that examines how inference about the IPCW estimates of the treatment‐group‐specific mean rates of decline in PTH changes as we vary the non‐ignorable selection bias parameter over a range of plausible values. Copyright © 2003 John Wiley & Sons, Ltd.
Stopping clinical trials because of treatment ineffectiveness: a comparison of a futility design with a method of stochastic curtailment
Authors: Whitehead John , Matsushita Tatsuru
Published: February 2003

This paper introduces a simple futility design that allows a comparative clinical trial to be stopped due to lack of effect at any of a series of planned interim analyses. Stopping due to apparent benefit is not permitted. The design is for use when any positive claim should be based on the maximum sample size, for example to allow subgroup analyses or the evaluation of safety or secondary efficacy responses. A final frequentist analysis can be performed that is valid for the type of design employed. Here the design is described and its properties are presented. Its advantages and disadvantages relative to the use of stochastic curtailment are discussed. Copyright © 2003 John Wiley & Sons, Ltd.
Variations in the arrangement of tonofilaments in the epidermis of teleost fish
Authors: WHITEAR Mary
Published: February 2003

Tonofilaments in epithelial cells of teleost skin can be aligned as bundles or skeins of appreciable bilk, or form a pattern of smaller bundles oriented in various directions, or there may be a condition where individual tonofilaments interlace. If sufficiently close together, interwoven tonofilaments can form a basket‐like structure, a “capsule”, proximally in the cell. This arrangement, previously known in epithelial cells of Myxinoids, occurs in localised sites in various teleosts of diverse taxonomic position, for instance in clupeids and gadids. A less intimate interlacing of cortical tonofilaments can accompany a modification of the perinuclear cytoplasm previously described, by light microscopy, as “vesiculated”, as in the middle layers of the epidermis in Periophthalmus. In head epidermis of Sprattus, the outer layers of cells contain proximal capsules, but the middle layers consist of flattened cells with a restricted perinuclear cytoplasm, peripheral tonofilaments, and a second population of filaments of a larger calibre. One implication of these results is that the cytoskeleton can undergo profound modification as cells progress from the basal to the superficial layers of the epidermis.
Social support networks and type of neurotic symptom among adults in British households
Authors: BRUGHA T. S. , MORGAN Z. , BEBBINGTON P. , JENKINS R. , LEWIS G. , FARRELL M. , MELTZER H.
Published: February 2003

Background. Current knowledge about associations between psychosocial factors and non-psychotic symptoms provide little information about their relationship to specific types of neurotic symptoms such as symptoms of fatigue, worry, phobic anxiety and obsessional symptoms.

Method. The British National Survey of Psychiatric Morbidity was based on a cross-sectional random sample of 10108 householders. Neurotic symptoms were established by lay interviewers using the revised fully structured Clinical Interview Schedule (CIS-R). Subjects were asked about perceived social support, the size of their close primary social network and sociodemographic attributes. To assess possible associations between specific types of neurotic symptoms and psychosocial risk factors multivariate Huber logistic models (a modified form of repeated measures design modelling) was used taking account of correlation between symptom types and sampling design including clustering.

Results. After controlling for sociodemographic factors the risk of having a high total CIS-R score ([ges ]12) was approximately doubled for both types of poor social functioning. Specific types of neurotic symptoms were associated both with a small primary group and with inadequate perceived social support. Depression, depressive ideas and panic symptoms had a higher prevalence in multivariate models. Poverty was associated with low support.

Conclusions. Associations with deficiencies in social support and self-reported neurotic symptoms are better explained by symptom type and in particular by depression than by the total number of symptoms. If confirmed by longitudinal study findings this knowledge could be used to inform the development of interventions to improve social support in order to reduce specific neurotic symptom types.
A randomized controlled trial to evaluate the effectiveness and cost-effectiveness of psychodynamic counselling for general practice patients with chronic depression
Authors: SIMPSON S. , CORNEY R. , FITZGERALD P. , BEECHAM J.
Published: February 2003

Background. Counsellors have been employed in general practice with little evidence of effectiveness. This study examined the effectiveness and cost-effectiveness of short-term counselling in general practice for patients with chronic depression either alone or combined with anxiety.

Method. A randomized controlled trial with an economic evaluation was carried out in Derbyshire. One hundred and forty-five patients were recruited at seven GP practices by screening using the Beck Depression Inventory. Both the experimental and control group received routine GP treatment but the experimental group were also referred to the practice counsellor. Depression, anxiety and other mental health symptoms, social and interpersonal functioning and social support were measured at baseline, 6 months and 12 months. Comprehensive costs were also estimated.

Results. There was an overall significant improvement in the actual scores over time, but there were no significant differences between the two groups on any of the measures at either 6 or 12 months. However fewer experimental group patients were still ‘cases’ on the BDI than controls at 12 months. There were no significant differences in the mean total costs, aggregate costs of services, or any service-group costs except for primary care, between the experimental and control groups over time.

Conclusions. This trial demonstrates only very limited evidence of improved outcomes in those referred to counselling and increased primary care treatment costs in the short-term. Stricter referral criteria to exclude the more severely depressed in the group (BDI[ges ]24) might have yielded more conclusive results.
Psychiatric adjustment in chronic fatigue syndrome of childhood and in juvenile idiopathic arthritis
Authors: RANGEL L. , GARRALDA M. E. , HALL A. , WOODHAM S.
Published: February 2003

Background. High rates of psychopathology and of personality problems have been reported in children and adolescents with chronic fatigue syndrome (CFS). It is not clear whether this is consequent on the experience of chronic physical ill health. We compare psychiatric adjustment in children with CFS and in children suffering from another chronic physical disorder (juvenile idiopathic arthritis or JIA).

Method. Our sample consisted of 28 children with CFS and 30 with JIA attending tertiary paediatric centres (age range, 11 to 18 years, mean 15, S.D. 2·3). In order to assess psychiatric status and functioning, we used the K-SADS psychiatric interviews, CGAS and Harter Self-Esteem Questionnaire with child subjects; behavioural questionnaires (CBCL) and child personality assessment interviews (PAS) with parent informants.

Results. Psychiatric disorders in the year prior to interview had been present significantly more commonly in the CFS group (72% v. 34% in JIA) and were more impairing to them (CGAS scores of 45 v. 77). Most common diagnoses in both groups were depressive and anxiety disorders. Personality problems were also significantly more frequent in CFS subjects (48% disorder and 26% difficulty v. 11% and 11% in JIA). There were few differences between the two groups in self-esteem.

Conclusions. Psychopathology and personality problems are common in children and adolescents with severe forms of CFS and cannot be explained strictly through the experience of chronic physical illness.
Height, weight and body mass index (BMI) in psychiatrically ill US Armed Forces personnel
Authors: WYATT R. J. , HENTER I. D. , MOJTABAI R. , BARTKO J. J.
Published: February 2003

Background. In both psychiatrically ill and psychiatrically healthy adults, the connection between health and individuals' height and weight has long been examined. Specifically, research on the idea that individuals with certain body types were prone to particular psychiatric diseases has been explored sporadically for centuries. The hypothesis that psychiatrically ill individuals were shorter and weighed less than psychiatrically healthy counterparts would correspond with the neurodevelopmental model of psychiatric disease.

Method. To evaluate possible links between psychiatric illness and physique, the height, weight and BMI of 7514 patients and 85 940 controls were compared. All subjects were part of the National Collaborative Study of Early Psychosis and Suicide (NCSEPS). Patients were US military active duty personnel hospitalized for either bipolar disorder, major depressive disorder, or schizophrenia and controls were psychiatrically-healthy US military active duty personnel matched for date of entry into the service.

Results. No consistent differences in height, weight or BMI were found between patients and controls, or between patient groups. Some weak ANOVA differences were found between age at the time of entering active duty and weight, as well as BMI, but not height.

Conclusions. Unlike most previous studies that have looked at the links between height and psychiatric illness, this study of the NCSEPS cohort found that, at entry into the US Armed Forces, there were no consistent decreases in height for patients with bipolar disorder, major depressive disorder or schizophrenia compared with a large control group. Furthermore, there were no consistent differences for weight or BMI.
The performance of the K6 and K10 screening scales for psychological distress in the Australian National Survey of Mental Health and Well-Being
Authors: FURUKAWA T. A. , KESSLER R. C. , SLADE T. , ANDREWS G.
Published: February 2003

Background. Two new screening scales for psychological distress, the K6 and K10, have been developed but their relative efficiency has not been evaluated in comparison with existing scales.

Method. The Australian National Survey of Mental Health and Well-Being, a nationally representative household survey, administered the WHO Composite International Diagnostic Interview (CIDI) to assess 30-day DSM-IV disorders. The K6 and K10 were also administered along with the General Health Questionnaire (GHQ-12), the current de facto standard of mental health screening. Performance of the three screening scales in detecting CIDI/DSM-IV mood and anxiety disorders was assessed by calculating the areas under receiver operating characteristic curves (AUCs). Stratum-Specific Likelihood Ratios (SSLRs) were computed to help produce individual-level predicted probabilities of being a case from screening scale scores in other samples.

Results. The K10 was marginally better than the K6 in screening for CIDI/DSM-IV mood and anxiety disorders (K10 AUC: 0·90, 95%CI: 0·89–0·91 versus K6 AUC: 0·89, 95%CI: 0·88–0·90), while both were significantly better than the GHQ-12 (AUC: 0·80, 95%CI: 0·78–0·82). The SSLRs of the K10 and K6 were more informative in ruling in or out the target disorders than those of the GHQ-12 at both ends of the population spectrum. The K6 was more robust than the K10 to subsample variation.

Conclusions. While the K10 might outperform the K6 in screening for severe disorders, the K6 is preferred in screening for any DSM-IV mood or anxiety disorder because of its brevity and consistency across subsamples. Precision of individual-level prediction is greatly improved by using polychotomous rather than dichotomous classification.
The economic cost of chronic fatigue and chronic fatigue syndrome in UK primary care
Authors: McCRONE P. , DARBISHIRE L. , RIDSDALE L. , SEED P.
Published: February 2003

Background. Chronic fatigue and chronic fatigue syndrome are most often encountered in primary care settings. Given the disabling nature of chronic fatigue it may have a substantial impact on service use and costs as well as on employment. This study estimates this impact.

Method. Patients presenting to general practitioners with unexplained chronic fatigue were recruited to the study. Service use over a 3 month period was measured and lost employment recorded. These data were used to estimate economic costs. Patients with chronic fatigue syndrome were compared to patients with only chronic fatigue using a multiple regression model with sample differences controlled.

Results. The mean total cost of services and lost employment across the sample was £1906 for the 3-month period with formal services accounting for 9·3% of this figure. Service use was higher for patients with chronic fatigue syndrome compared to those with chronic fatigue alone. Total 3-month costs were on average higher for chronic fatigue syndrome (£3515 v. £1176) but when sample differences were taken account of the mean difference was reduced to £1406 (P=0·086). Over 90% of the cost was accounted for by care provided by friends and family members and by lost employment. Patients with dependants had significantly higher costs than those with none and costs were also significantly higher for greater levels of functional impairment.

Conclusion. Chronic fatigue imposes substantial economic costs on society, mainly in the form of informal care and lost employment. Treatments need to be developed which recognize these impacts.
Predictors of outcome in a fatigued population in primary care following a randomized controlled trial
Authors: CHALDER T. , GODFREY E. , RIDSDALE L. , KING M. , WESSELY S.
Published: February 2003

Background. The objective of this study was to examine factors that predicted outcome in a chronically fatigued group of patients who were randomized to cognitive behaviour therapy or counselling in primary care.

Method. Illness perceptions, attributions, fatigue, disability and demographic variables were recorded at assessment and levels of fatigue and disability were measured at 6 months post randomization. Logistic regression was used to examine associations.

Results. Factors that predicted a poor outcome (four or more on the fatigue questionnaire) were: poor social adjustment at assessment; the patients self-report that they had never seen the GP for an emotional reason; a physical illness attribution; and, a long perceived future illness duration.

Conclusions. Patients who are more psychologically minded are more likely to improve with psychological treatments in primary care. General practitioners need to assess this before referring to an appropriate therapist.
Costs, correlates and consequences of fatigue in children and adults
Authors: WHITE PETER D.
Published: February 2003

The problems of understanding what causes chronic fatigue, its relationship to psychiatric disorders, and how best to treat it continue to baffle and bemuse clinicians and patients alike (Report to the CMO, 2002; Stanley et al. 2002). This edition of the journal carries four original papers that provide much needed knowledge in a subject riddled by polemic and prejudice (White, 2002).
Analytical integral equation theory for a restricted primitive model of polyelectrolytes and counterions within the mean spherical approximation. II. Radial distribution functions
Authors: von Solms N. , Chiew Y. C.
Published: February 2003

We have solved a polymerizing version of the mean spherical approximation for polyelectrolytes. The polyelectrolytes are modeled as tangentially-bonded hard-sphere segments interacting via the Coulombic potential in a continuous medium with dielectric constant. Analytical solutions for thermodynamic properties and radial distribution functions at contact, as well as numerical solutions using a multiple-variable version of the Perram algorithm for radial distribution functions at separations beyond the core, are obtained for some specific systems (negatively charged chains of various length and counterions). Comparisons were made with published experimental data for osmotic pressure and with computer simulations for radial distribution functions. Good agreement is found for the osmotic pressure at all ranges of density. Good agreement is found for the radial distribution functions at moderate to high density.