bluuebunny/crossref_metadata_2025 huggingface dataset:
Automatic selection of representative proteins for bacterial phylogeny
Authors: Bern Marshall , Goldberg David
Published: June 2005

Background

Although there are now about 200 complete bacterial genomes in GenBank, deep bacterial phylogeny remains a difficult problem, due to confounding horizontal gene transfers and other phylogenetic "noise". Previous methods have relied primarily upon biological intuition or manual curation for choosing genomic sequences unlikely to be horizontally transferred, and have given inconsistent phylogenies with poor bootstrap confidence.

Results

We describe an algorithm that automatically picks "representative" protein families from entire genomes for use as phylogenetic characters. A representative protein family is one that, taken alone, gives an organismal distance matrix in good agreement with a distance matrix computed from all sufficiently conserved proteins. We then use maximum-likelihood methods to compute phylogenetic trees from a concatenation of representative sequences. We validate the use of representative proteins on a number of small phylogenetic questions with accepted answers. We then use our methodology to compute a robust and well-resolved phylogenetic tree for a diverse set of sequenced bacteria. The tree agrees closely with a recently published tree computed using manually curated proteins, and supports two proposed high-level clades: one containing Actinobacteria, Deinococcus, and Cyanobacteria ("Terrabacteria"), and another containing Planctomycetes and Chlamydiales.

Conclusion

Representative proteins provide an effective solution to the problem of selecting phylogenetic characters.
Preclinical evaluation of the proteasome inhibitor bortezomib in cancer therapy
Authors: Boccadoro Mario , Morgan Gareth , Cavenagh Jamie
Published: June 2005

Bortezomib is a highly selective, reversible inhibitor of the 26S proteasome that is indicated for single-agent use in the treatment of patients with multiple myeloma who have received at least 2 prior therapies and are progressing on their most recent therapy. Clinical investigations have been completed or are under way to evaluate the safety and efficacy of bortezomib alone or in combination with chemotherapy in multiple myeloma, both at relapse and presentation, as well as in other cancer types. The antiproliferative, proapoptotic, antiangiogenic, and antitumor activities of bortezomib result from proteasome inhibition and depend on the altered degradation of a host of regulatory proteins. Exposure to bortezomib has been shown to stabilize p21, p27, and p53, as well as the proapoptotic Bid and Bax proteins, caveolin-1, and inhibitor κB-α, which prevents activation of nuclear factor κB-induced cell survival pathways. Bortezomib also promoted the activation of the proapoptotic c-Jun-NH2terminal kinase, as well as the endoplasmic reticulum stress response. The anticancer effects of bortezomib as a single agent have been demonstrated in xenograft models of multiple myeloma, adult T-cell leukemia, lung, breast, prostate, pancreatic, head and neck, and colon cancer, and in melanoma. In these preclinicalin vivostudies, bortezomib treatment resulted in decreased tumor growth, angiogenesis, and metastasis, as well as increased survival and tumor apoptosis. In severalin vitroand/orin vivocancer models, bortezomib has also been shown to enhance the antitumor properties of several antineoplastic treatments. Importantly, bortezomib was generally well tolerated and did not appear to produce additive toxicities when combined with other therapies in the dosing regimens used in these preclinicalin vivoinvestigations. These findings provide a rationale for further clinical trials using bortezomib alone or in combination regimens with chemotherapy, radiation therapy, immunotherapy, or novel agents in patients with hematologic malignancies or solid tumors.
Use of plant stanol ester margarine among persons with and without cardiovascular disease: Early phases of the adoption of a functional food in Finland
Authors: Simojoki Meri , Luoto Riitta , Uutela Antti , Rita Hannu , Boice John D , McLaughlin Joseph K , Puska Pekka
Published: June 2005

Background

The plant stanol ester margarine Benecol® is a functional food that has been shown to lower effectively serum total and LDL-cholesterol. The purpose of this post-marketing study is to characterize users of plant stanol ester margarine with and without cardiovascular disease.

Methods

A cohort of plant stanol ester margarine users was established based on a compilation of 15 surveys conducted by the National Public Health Institute in Finland between 1996–2000. There were 29 772 subjects aged 35–84 years in the cohort. The users of plant stanol ester margarine were identified by the type of bread spread used.

Results

The plant stanol ester margarine was used as bread spread by 1332 (4.5%) subjects. Almost half (46%) of the users reported a history of cardiovascular disease. Persons with cardiovascular disease were more likely to use plant stanol ester margarine (8%) than persons without cardiovascular disease (3%). Users with and without cardiovascular disease seemed to share similar characteristics.

In particular, they were elderly people with otherwise healthy life-styles and diet. They were less likely smokers, more likely physically active and less likely obese than nonusers. The users reported being in good or average health in general and having used cholesterol-lowering drugs.

Conclusion

Plant stanol ester margarine seems to be used by persons for whom it was designed and in a way it was meant: as part of efforts for cardiovascular disease risk reduction.
Neighborhood size and local geographic variation of health and social determinants
Authors: Ali Mohammad , Park Jin-Kyung , Thiem Vu Dinh , Canh Do Gia , Emch Michael , Clemens John D
Published: June 2005

Background

Spatial filtering using a geographic information system (GIS) is often used to smooth health and ecological data. Smoothing disease data can help us understand local (neighborhood) geographic variation and ecological risk of diseases. Analyses that use small neighborhood sizes yield individualistic patterns and large sizes reveal the global structure of data where local variation is obscured. Therefore, choosing an optimal neighborhood size is important for understanding ecological associations with diseases. This paper uses Hartley's test of homogeneity of variance (Fmax) as a methodological solution for selecting optimal neighborhood sizes. The data from a study area in Vietnam are used to test the suitability of this method.

Results

The Hartley's Fmax test was applied to spatial variables for two enteric diseases and two socioeconomic determinants. Various neighbourhood sizes were tested by using a two step process to implement the Fmaxtest. First the variance of each neighborhood was compared to the highest neighborhood variance (upper, Fmax1) and then they were compared with the lowest neighborhood variance (lower, Fmax2). A significant value of Fmax1 indicates that the neighborhood does not reveal the global structure of data, and in contrast, a significant value in Fmax2 implies that the neighborhood data are not individualistic. The neighborhoods that are between the lower and the upper limits are the optimal neighbourhood sizes.

Conclusion

The results of tests provide different neighbourhood sizes for different variables suggesting that optimal neighbourhood size is data dependent. In ecology, it is well known that observation scales may influence ecological inference. Therefore, selecting optimal neigborhood size is essential for understanding disease ecologies. The optimal neighbourhood selection method that is tested in this paper can be useful in health and ecological studies.
Inflammatory fibroid polyp of the oesophagus
Authors: Godey Shashi Kanth , Diggory Robert T
Published: May 2005

Background

Inflammatory fibroid polyp of the oesophagus is an uncommon lesion and very rarely it grows rapidly.

Case presentation

We present the case of a patient with a rapidly growing inflammatory fibroid polyp (IFP) of the oesophagus, which showed up within five months after a normal endoscopy.

Conclusion

The treatment of IFP is by surgical excision, either open or endoscopic. Laser or other form of ablative treatment like thermo cautery can also be tried.
Cu/Zn superoxide dismutase expression in the postnatal rat brain following an excitotoxic injury
Authors: Peluffo Hugo , Acarin Laia , Faiz Maryam , Castellano Bernardo , Gonzalez Berta
Published: June 2005

Background

In the nervous system, as in other organs, Cu/Zn superoxide dismutase (Cu/Zn SOD) is a key antioxidant enzyme involved in superoxide detoxification in normal cellular metabolism and after cell injury. Although it has been suggested that immature brain has a different susceptibility to oxidative damage than adult brain, the distribution and cell-specific expression of this enzyme in immature brain and after postnatal brain damage has not been documented.

Methods

In this study, we used immunohistochemistry and western blot to analyze the expression of Cu/Zn SOD in intact immature rat brain and in immature rat brain after an NMDA-induced excitotoxic cortical injury performed at postnatal day 9. Double immunofluorescence labelling was used to identify Cu/Zn SOD-expressing cell populations.

Results

In intact immature brain, Cu/Zn SOD enzyme was widely expressed at high levels in neurons mainly located in cortical layers II, III and V, in the sub-plate, in the pyriform cortex, in the hippocampus, and in the hypothalamus. Glial fibrillary acidic protein-positive cells only showed Cu/Zn SOD expression in the glia limitans and in scattered cells of the ventricle walls. No expression was detected in interfascicular oligodendroglia, microglia or endothelial cells. Following excitotoxic damage, neuronal Cu/Zn SOD was rapidly downregulated (over 2–4 hours) at the injection site before neurodegeneration signals and TUNEL staining were observed. Later, from 1 day post-lesion onward, an upregulation of Cu/Zn SOD was found due to increased expression in astroglia. A further increase was observed at 3, 5 and 7 days that corresponded to extensive induction of Cu/Zn SOD in highly reactive astrocytes and in the astroglial scar.

Conclusion

We show here that, in the intact immature brain, the expression of Cu/Zn SOD was mainly found in neurons. When damage occurs, a strong and very rapid downregulation of this enzyme precedes neuronal degeneration, and is followed by an upregulation of Cu/Zn SOD in astroglial cells.
Influence of a portable audio-biofeedback device on structural properties of postural sway
Authors: Dozza Marco , Chiari Lorenzo , Chan Becky , Rocchi Laura , Horak Fay B , Cappello Angelo
Published: June 2005

Background

Good balance depends on accurate and adequate information from the senses. One way to substitute missing sensory information for balance is with biofeedback technology. We previously reported that audio-biofeedback (ABF) has beneficial effects in subjects with profound vestibular loss, since it significantly reduces body sway in quiet standing tasks.

Methods

In this paper, we present the effects of a portable prototype of an ABF system on healthy subjects' upright stance postural stability, in conditions of limited and unreliable sensory information. Stabilogram diffusion analysis, combined with traditional center of pressure analysis and surface electromyography, were applied to the analysis of quiet standing tasks on a Temper foam surface with eyes closed.

Results

These analyses provided new evidence that ABF may be used to treat postural instability. In fact, the results of the stabilogram diffusion analysis suggest that ABF increased the amount of feedback control exerted by the brain for maintaining balance. The resulting increase in postural stability was not at the expense of leg muscular activity, which remained almost unchanged.

Conclusion

Examination of the SDA and the EMG activity supported the hypothesis that ABF does not induce an increased stiffness (and hence more co-activation) in leg muscles, but rather helps the brain to actively change to a more feedback-based control activity over standing posture.
Peptide inhibitors of dengue virus and West Nile virus infectivity
Authors: Hrobowski Yancey M , Garry Robert F , Michael Scott F
Published: June 2005

Viral fusion proteins mediate cell entry by undergoing a series of conformational changes that result in virion-target cell membrane fusion. Class I viral fusion proteins, such as those encoded by influenza virus and human immunodeficiency virus (HIV), contain two prominent alpha helices. Peptides that mimic portions of these alpha helices inhibit structural rearrangements of the fusion proteins and prevent viral infection. The envelope glycoprotein (E) of flaviviruses, such as West Nile virus (WNV) and dengue virus (DENV), are class II viral fusion proteins comprised predominantly of beta sheets. We used a physio-chemical algorithm, the Wimley-White interfacial hydrophobicity scale (WWIHS) [1] in combination with known structural data to identify potential peptide inhibitors of WNV and DENV infectivity that target the viral E protein. Viral inhibition assays confirm that several of these peptides specifically interfere with target virus entry with 50% inhibitory concentration (IC50) in the 10 μM range. Inhibitory peptides similar in sequence to domains with a significant WWIHS scores, including domain II (IIb), and the stem domain, were detected. DN59, a peptide corresponding to the stem domain of DENV, inhibited infection by DENV (>99% inhibition of plaque formation at a concentrations of <25 μM) and cross-inhibition of WNV fusion/infectivity (>99% inhibition at <25 μM) was also demonstrated with DN59. However, a potent WNV inhibitory peptide, WN83, which corresponds to WNV E domain IIb, did not inhibit infectivity by DENV. Additional results suggest that these inhibitory peptides are noncytotoxic and act in a sequence specific manner. The inhibitory peptides identified here can serve as lead compounds for the development of peptide drugs for flavivirus infection.
Intrapulmonary percussive ventilation in acute exacerbations of COPD patients with mild respiratory acidosis: a randomized controlled trial [ISRCTN17802078]
Authors: Vargas Frédéric , Bui Hoang Nam , Boyer Alexandre , Salmi Louis Rachid , Gbikpi-Benissan Georges , Guenard Hervé , Gruson Didier , Hilbert Gilles
Published: June 2005

Introduction

We hypothesized that the use of intrapulmonary percussive ventilation (IPV), a technique designed to improve mucus clearance, could prove effective in avoiding further deterioration in patients with acute exacerbations of chronic obstructive pulmonary disease (COPD) with mild respiratory acidosis.

Methods

The study was performed in a medical intensive care unit of a university hospital. Thirty-three patients with exacerbations of COPD with a respiratory frequency ≥ 25/min, a PaCO2 > 45 Torr and 7.35 ≤ pH ≤ 7.38 were included in the study. Patients were randomly assigned to receive either standard treatment (control group) or standard treatment plus IPV (IPV group). The IPV group underwent two daily sessions of 30 minutes performed by a chest physiotherapist through a full face mask. The therapy was considered successful when both worsening of the exacerbation and a decrease in pH to under 7.35, which would have required non-invasive ventilation, were avoided.

Results

Thirty minutes of IPV led to a significant decrease in respiratory rate, an increase in PaO2 and a decrease in PaCO2 (p < 0.05). Exacerbation worsened in 6 out of 17 patients in the control group versus 0 out of 16 in the IPV group (p < 0.05). The hospital stay was significantly shorter in the IPV group than in the control group (6.8 ± 1.0 vs. 7.9 ± 1.3 days, p < 0.05).

Conclusion

IPV is a safe technique and may prevent further deterioration in patients with acute exacerbations of COPD with mild respiratory acidosis.
Intensive care unit delirium is an independent predictor of longer hospital stay: a prospective analysis of 261 non-ventilated patients
Authors: Thomason Jason WW , Shintani Ayumi , Peterson Josh F , Pun Brenda T , Jackson James C , Ely E Wesley
Published: June 2005

Introduction

Delirium occurs in most ventilated patients and is independently associated with more deaths, longer stay, and higher cost. Guidelines recommend monitoring of delirium in all intensive care unit (ICU) patients, though few data exist in non-ventilated patients. The study objective was to determine the relationship between delirium and outcomes among non-ventilated ICU patients.

Method

A prospective cohort investigation of 261 consecutively admitted medical ICU patients not requiring invasive mechanical ventilation during hospitalization at a tertiary-care, university-based hospital between February 2002 and January 2003. ICU nursing staff assessed delirium and level of consciousness at least twice per day using the Confusion Assessment Method for the ICU (CAM-ICU) and Richmond Agitation-Sedation Scale (RASS). Cox regression with time-varying covariates was used to determine the independent relationship between delirium and clinical outcomes.

Results

Of 261 patients, 125 (48%) experienced at least one episode of delirium. Patients who experienced delirium were older (mean ± SD: 56 ± 18 versus 49 ± 17 years; p = 0.002) and more severely ill as measured by Acute Physiology and Chronic Health Evaluation II (APACHE II) scores (median 15, interquartile range (IQR) 10–21 versus 11, IQR 6–16; p < 0.001) compared to their non-delirious counterparts. Patients who experienced delirium had a 29% greater risk of remaining in the ICU on any given day (compared to patients who never developed delirium) even after adjusting for age, gender, race, Charlson co-morbidity score, APACHE II score, and coma (hazard ratio (HR) 1.29; 95% confidence interval (CI) 0.98–1.69, p = 0.07). Similarly, patients who experienced delirium had a 41% greater risk of remaining in the hospital after adjusting for the same covariates (HR 1.41; 95% CI 1.05–1.89, p = 0.023). Hospital mortality was higher among patients who developed delirium (24/125, 19%) versus patients who never developed delirium (8/135, 6%), p = 0.002; however, time to in-hospital death was not significant the adjusted (HR 1.27; 95% CI 0.55–2.98, p = 0.58).

Conclusion

Delirium occurred in nearly half of the non-ventilated ICU patients in this cohort. Even after adjustment for relevant covariates, delirium was found to be an independent predictor of longer hospital stay.
Mechanisms of aging in senescence-accelerated mice
Authors: Carter Todd A , Greenhall Jennifer A , Yoshida Shigeo , Fuchs Sebastian , Helton Robert , Swaroop Anand , Lockhart David J , Barlow Carrolee
Published: June 2005

Background

Progressive neurological dysfunction is a key aspect of human aging. Because of underlying differences in the aging of mice and humans, useful mouse models have been difficult to obtain and study. We have used gene-expression analysis and polymorphism screening to study molecular senescence of the retina and hippocampus in two rare inbred mouse models of accelerated neurological senescence (SAMP8 and SAMP10) that closely mimic human neurological aging, and in a related normal strain (SAMR1) and an unrelated normal strain (C57BL/6J).

Results

The majority of age-related gene expression changes were strain-specific, with only a few common pathways found for normal and accelerated neurological aging. Polymorphism screening led to the identification of mutations that could have a direct impact on important disease processes, including a mutation in a fibroblast growth factor gene, Fgf1, and a mutation in and ectopic expression of the gene for the chemokine CCL19, which is involved in the inflammatory response.

Conclusion

We show that combining the study of inbred mouse strains with interesting traits and gene-expression profiling can lead to the discovery of genes important for complex phenotypes. Furthermore, full-genome polymorphism detection, sequencing and gene-expression profiling of inbred mouse strains with interesting phenotypic differences may provide unique insights into the molecular genetics of late-manifesting complex diseases.
Natural antisense transcripts with coding capacity in Arabidopsismay have a regulatory role that is not linked to double-stranded RNA degradation
Authors: Jen Chih-Hung , Michalopoulos Ioannis , Westhead David R , Meyer Peter
Published: June 2005

Background

Overlapping transcripts in antisense orientation have the potential to form double-stranded RNA (dsRNA), a substrate for a number of different RNA-modification pathways. One prominent route for dsRNA is its breakdown by Dicer enzyme complexes into small RNAs, a pathway that is widely exploited by RNA interference technology to inactivate defined genes in transgenic lines. The significance of this pathway for endogenous gene regulation remains unclear.

Results

We have examined transcription data for overlapping gene pairs in Arabidopsis thaliana. On the basis of an analysis of transcripts with coding regions, we find the majority of overlapping gene pairs to be convergently overlapping pairs (COPs), with the potential for dsRNA formation. In all tissues, COP transcripts are present at a higher frequency compared to the overall gene pool. The probability that both the sense and antisense copy of a COP are co-transcribed matches the theoretical value for coexpression under the assumption that the expression of one partner does not affect the expression of the other. Among COPs, we observe an over-representation of spliced (intron-containing) genes (90%) and of genes with alternatively spliced transcripts. For loci where antisense transcripts overlap with sense transcript introns, we also find a significant bias in favor of alternative splicing and variation of polyadenylation.

Conclusion

The results argue against a predominant RNA degradation effect induced by dsRNA formation. Instead, our data support alternative roles for dsRNAs. They suggest that at least for a subgroup of COPs, antisense expression may induce alternative splicing or polyadenylation.
Bipolar disorder and childbirth: the importance of recognising risk
Authors: Jones Ian , Craddock Nick
Published: June 2005

In October 2003 the report was published of an inquiry into the death of a psychiatric colleague that raised a number of important questions – not least regarding our management of women with bipolar disorder in pregnancy and the postpartum period (North East London Strategic Health Authority, 2003). Dr Daksha Emson took the life of herself and her 3-month-old daughter, Freya. This tragedy took place during a psychotic episode triggered by childbirth and was a consequence of her history of bipolar affective disorder. Sadly, the case of Dr Emson is far from unique. The Confidential Enquiries into Maternal Deaths (2001) found that suicide had become the leading cause of maternal mortality in the UK, accounting for 28% of maternal deaths (Oates, 2003a). The majority of the women who died by suicide suffered an abrupt onset of a severe psychotic illness within days of childbirth – a ‘puerperal psychosis', to use the traditional nosological label. For some women an episode of puerperal psychosis will be the first experience of severe mental illness, but a significant proportion of women will have had previous episodes. In the Confidential Enquiries into Maternal Deaths (2001), for example, 46% of the women who killed themselves (the majority by violent means) had previously been in contact with psychiatric services – and half of these had had a previous admission with a severe episode of illness following childbirth (Oates, 2003b). In many maternal suicides, therefore, the occurrence of an episode of severe post-partum psychiatric illness is an eminently predictable event. Although some women in the report were in contact with psychiatric services, none had received a detailed risk assessment, none had a formal management plan, and none was under close surveillance in the puerperium. It is also worth noting that none of the women in the cases of maternal suicide reported in the Confidential Enquiries was under the care of a mother and baby unit or perinatal psychiatric service (Oates, 2003a). The report on maternal deaths in 2000–2002 has now been published (Confidential Enquiries into Maternal Deaths, 2004) and, sadly, the findings are similar.
Metabolic syndrome and schizophrenia
Authors: Thakore Jogin H.
Published: June 2005

Metabolic syndrome – a cluster of disorders comprising obesity (central and abdominal), dyslipidaemias, glucose intolerance, insulin resistance (or hyperinsulinaemia) and hypertension – is highly predictive of type 2 diabetes mellitus and cardiovascular disease. In order to improve detection of this syndrome and estimate its prevalence, both the World Health Organization (Alberti & Zimmet, 1998) and the National Cholesterol Education Program Adult Treatment Panel (National Cholesterol Education Program, 2001) have provided working criteria for its diagnosis (the World Health Organization criteria are reproduced in an appendix to this paper; copyright restrictions prevent the inclusion here of the National Cholesterol Education Program criteria). Using the latter criteria, Heiskanen et al (2003) found that the frequency of metabolic syndrome was 2–4 times higher in a group of people with schizophrenia, treated with both atypical and typical neuroleptics, than in an appropriate reference population.
‘Goodbye and good luck’: the mental health needs and treatment experiences of British ex-service personnel
Authors: Iversen Amy , Dyson Claire , Smith Naomi , Greenberg Neil , Walwyn Rebecca , Unwin Catherine , Hull Lisa , Hotopf Matthew , Dandeker Christopher , Ross John , Wessely Simon
Published: June 2005

Background

Little is known about the psychological health or treatment experiences of those who have left the British armed forces.

Aims

To describe the frequency and associations of common mental disorders and help-seeking behaviours in a representative sample of UK veterans at high risk of mental health problems.

Method

A cross-sectional telephone survey of 496 ‘vulnerable’ ex-service personnel selected from an existing epidemiological military cohort.

Results

The response rate was 64%; 44% of these had a psychiatric diagnosis, most commonly depression. Those with a diagnosis were more likely to be of lower rank and divorced or separated. Just over half of those with self-reported mental health problems were currently seeking help, most from their general practitioners. Most help-seekers received treatment, usually medication; 28% were in touch with a service charity and 4% were receiving cognitive-behavioural therapy.

Conclusions

Depression is more common than post-traumatic stress disorder in UK ex-service personnel. Only about half of those who have a diagnosis are seeking help currently, and few see specialists.
Symptoms of post-traumatic stress disorder after non-traumatic events: evidence from an open population study
Authors: Mol Saskia S. L. , Arntz Arnoud , Metsemakers Job F. M. , Dinant Geert-Jan , Vilters-van Montfort Pauline A. P. , Knottnerus J. André
Published: June 2005

Background

Post-traumatic stress disorder (PTSD) is the only psychiatric condition that requires a specific event to have occurred for its diagnosis.

Aims

To gather evidence from the adult general population on whether life events (e. g. divorce, unemployment) generate as many symptoms of post-traumatic stress as traumatic events (e. g. accidents, abuse).

Method

Data on demographic characteristics and history of stressful events were collected through a written questionnaire sent to a random sample of 2997 adults. Respondents also filled out a PTSD symptom checklist, keeping in mind their worst event. Mean PTSD scores were compared, controlling for differences between the two groups. Differences in item scores and in the distribution of the total PTSD scores were analysed.

Results

Of the 1498 respondents, 832 were eligible for inclusion in our analysis. For events from the past 30 years the PTSD scores were higher after life events than after traumatic events; for earlier events the scores were the same for both types of events. These findings could not be explained by differences in demographics, history of stressful events, individual item scores, or the distribution of the total PTSD scores.

Conclusions

Life events can generate at least as many PTSD symptoms as traumatic events. Our findings call for further studies on the specificity of traumatic events as a cause of PTSD.
Outcome in severe irritable bowel syndrome with and without accompanying depressive, panic and neurasthenic disorders
Authors: Creed Francis , Ratcliffe Joy , Fernandes Lakshmi , Palmer Stephen , Rigby Christine , Tomenson Barbara , Guthrie Elspeth , Read Nicholas , Thompson David G.
Published: June 2005

Background

Irritable bowel syndrome often leads to impaired functioning.

Aims

To assess the contribution of psychiatric disorders to impaired outcome in severe irritable bowel syndrome.

Method

Patients with severe irritable bowel syndrome entering a psychological treatment trial (n=257) were interviewed using the Schedules for Clinical Assessment in Neuropsychiatry. Outcomes were number of days of restricted activity, role limitation (physical) score of the Short Form Health Survey and costs.

Results

At baseline, depressive disorder (29% of patients), panic (12%) and neurasthenia (35%) were associated with impairment; number of psychiatric disorders was associated in a dose–response fashion (P=0. 005). At follow-up, depressive disorder and neurasthenia were associated with role limitation score. Improved depression was associated with improved role functioning.

Conclusions

Depressive, panic and neurasthenic disorders contribute to poor outcomes in severe irritable bowel syndrome, and appropriate treatment should be available to these patients.
Personality subtypes in eating disorders: validation of a classification in a naturalistic sample
Authors: Thompson-Brenner Heather , Westen Drew
Published: June 2005

Background

Research has identified three personality subtypes in patients with eating disorders: emotionally dysregulated, constricted and high-functioning/perfectionistic.

Aims

To see whether the subtypes are distinguished in ways indicative of valid classification, notably in patterns of adaptive functioning, comorbidity, treatment response and therapeutic interventions.

Method

A random sample of experienced clinicians provided data on 145 patients with bulimic symptoms, including data on eating disorder symptoms, DSM–IV comorbidity, personality pathology, treatment response and treatment interventions.

Results

Patients categorised as dysregulated had the poorest functioning, most comorbidity and worst outcome, followed by patients in the constricted and high-functioning groups. The three subtypes elicited different therapeutic interventions and accounted for substantial incremental variance in outcome, holding constant the severity of eating disorder symptoms and presence of other Axis I disorders.

Conclusions

The data provide accumulating evidence for the validity of three personality subtypes in patients with eating disorders.
Obsessions and compulsions in Asperger syndrome and high-functioning autism
Authors: Russell Ailsa J. , Mataix-Cols David , Anson Martin , Murphy Declan G. M.
Published: June 2005

Background

Obsessive–compulsive behaviours are common and disabling in autistic-spectrum disorders (ASD) but little is known about how they compare with those experienced by people with obsessive–compulsive disorder (OCD).

Aim

To make such a comparison.

Method

A group of adults with high-functioning ASD (n=40) were administered the Yale–Brown Obsessive–Compulsive Scale and Symptom Checklist and their symptoms compared with a gender-matched group of adults with a primary diagnosis of OCD (n=45). OCD symptoms were carefully distinguished from stereotypic behaviours and interests usually displayed by those with ASD.

Results

The two groups had similar frequencies of obsessive–compulsive symptoms, with only somatic obsessions and repeating rituals being more common in the OCD group. The OCD group had higher obsessive–compulsive symptom severity ratings but up to 50% of the ASD group reported at least moderate levels of interference from their symptoms.

Conclusions

Obsessions and compulsions are both common in adults with high-functioning ASD and are associated with significant levels of distress.
Going to war does not have to hurt: preliminary findings from the British deployment to Iraq
Authors: Hughes Jamie Hacker , Cameron Fiona , Eldridge Rod , Devon Madeleine , Wessely Simon , Greenberg Neil
Published: June 2005

We carried out a brief longitudinal mental health screen of 254 members of the UK's Air Assault Brigade before and after deployment to Iraq last year. Analysis of General Health Questionnaire (GHQ–28) scores before and after deployment revealed a lower score after deployment (mean difference=0. 93, 95% CI 0. 35–1. 52). This indicated a highly significant relative improvement in mental health (P < 0. 005). Moreover, only 9 of a larger sample of 421 (2%) exceeded cut-off criteria on the Trauma Screening Questionnaire. These findings suggest that war is not necessarily bad for psychological health.
Self-harm in older people with depression
Authors: Dennis Michael , Wakefield Penny , Molloy Caroline , Andrews Harry , Friedman Trevor
Published: June 2005

Studying non-fatal self-harm in older adults may provide insight into suicidal behaviour in this age group. The objectives of the study were to determine clinical factors that might help to differentiate those older adults with depression who are most at risk of self-harm and suicide. We examined social factors, life events, hopelessness and other depression symptoms in a group of 48 older people with depression referred following an episode of self-harm compared with 50 similarly aged people with depression who had no history of self-harm. The groups were similar in many respects, although those in the self-harm group were more likely to have a poorly integrated social network and were more hopeless.
Physical health of patients in rehabilitation and recovery: a survey of case note records
Authors: Greening Jayne
Published: June 2005

Aims and Method

The aim of this survey was to determine details recorded about the physical health of patients in rehabilitation and recovery. All medical and nursing notes from January 1998 to March 2003 were reviewed. Case notes from 63 patients were studied.

Results

There was mention in less than 13 of the patients' notes (18%) of smoking, diet, exercise or prolactin levels; weight, blood pressure, electrocardiogram, erythrocyte sedimentation rate or lipids were mentioned in less than 20 (30%). A blood sugar test was performed in only 16 patients (25%) in the past year and 38 patients (59%) had a record of a test in the past 5 years. These results suggest that there is inadequate recording of the physical health parameters in patients in rehabilitation and recovery.

Clinical Implications

The physical healthcare of patients with schizophrenia is prioritised in the National Institute for Clinical Excellence (NICE) clinical guidelines, which specifically mention the monitoring of endocrine disorders such as diabetes and hyperprolactinaemia, cardiovascular risk factors, such as blood pressure and lipids, and lifestyle factors such as smoking. Routine recording of physical health indices should be mandatory and staff may need further training to enable them to do this.
The Family Adaptability and Cohesion Evaluation Scale (FACES): an instrument worthy of rehabilitation?
Authors: Place Maurice , Hulsmeier Jessica , Brownrigg Allan , Soulsby Alison
Published: June 2005

Aims and Method

There have been a variety of instruments developed for evaluating family functioning, but no specific measure has emerged as appropriate for routine clinical use. The Family Adaptability and Cohesion Evaluation Scale (FACES) was viewed as a useful tool for a period, but has been less popular of late. This paper looks at its use in families with two very different types of problem to assess its discriminatory ability.

Results

Mothers with depression whose children were not showing mental health difficulties reported a very different pattern of family functioning from those whose children were showing chronic school refusal.

Clinical Implications

The FACES is capable of discriminating between different patterns of family functioning. Its ease of administration, and the information it provides, should recommend it for wider use in clinical settings.
What every psychiatrist should know about buprenorphine in substance misuse
Authors: Taikato Matira , Kidd Brian , Baldacchino Alex
Published: June 2005

Buprenorphine is prescribed as a treatment for opioid dependence (Barnett et al, 2001; Lintzeris et al, 2002). Methadone substitute prescribing is the primary maintenance treatment in Britain and is well established (Ward, 1997). Despite the advantages of methadone maintenance there are associated disadvantages, including potential death following overdose, the inconvenience of daily dosing, the risk of the drug being used by others and stigma (Walsh, 1994).
PDGFRA Mutations in Gastrointestinal Stromal Tumors: Frequency, Spectrum and In Vitro Sensitivity to Imatinib
Authors: Corless Christopher L. , Schroeder Arin , Griffith Diana , Town Ajia , McGreevey Laura , Harrell Patina , Shiraga Sharon , Bainbridge Troy , Morich Jason , Heinrich Michael C.
Published: June 2005

Purpose

Gastrointestinal stromal tumors (GISTs) commonly harbor oncogenic mutations of the KIT tyrosine kinase, which is a target for the kinase inhibitor imatinib. A subset of GISTs, however, contains mutations in the homologous kinase platelet derived growth factor receptor alpha (PDGFRA), and the most common of these mutations is resistant to imatinib in vitro. Little is known of the other types of PDGFRA mutations that occur in GISTs.

Materials and Methods

We determined the KIT and PDGFRA mutation status of 1,105 unique GISTs using a combination of denaturing high-performance liquid chromatography and direct sequencing.

Results

There were 80 tumors (7.2%) with a PDGFRA mutation: 66 in exon 18, 11 in exon 12, and three in exon 14. Transient expression of representative PDGFRA isoforms in CHO cells revealed imatinib sensitivity of exon 12 mutations (SPDHE566-571R and insertion ER561-562) and an exon 14 substitution (N659K). However, most isoforms with a substitution involving codon D842 in exon 18 (D842V, RD841-842KI, DI842-843IM) were resistant to the drug, with the exception of D842Y. Interestingly, other mutations in exon 18 (D846Y, N848K, Y849K and HDSN845-848P) were all imatinib sensitive. Proliferation studies with BA/F3 cell lines stably expressing selected PDGFRA mutant isoforms supported these findings.

Conclusion

Including our cases, there are 289 reported PDGFRA-mutant GISTs, of which 181 (62.6%) had the imatinib-resistant substitution D842V. However, our findings suggest that more than one third of GISTs with PDGFRA mutations may respond to imatinib and that mutation screening may be helpful in the management of these tumors.
A Point Mutation in the Human Melanin Concentrating Hormone Receptor 1 Reveals an Important Domain for Cellular Trafficking
Authors: Fan Jun , Perry Stephen J. , Gao Yinghong , Schwarz David A. , Maki Richard A.
Published: June 2005

G protein-coupled receptors (GPCRs) are heptahelical integral membrane proteins that require cell surface expression to elicit their effects. The lack of appropriate expression of GPCRs may be the underlying cause of a number of inherited disorders. There is evidence that newly synthesized GPCRs must attain a specific conformation for their correct trafficking to the cell surface. In this study, we show that a single point mutation in human melanin-concentrating hormone receptor (hMCHR1) at position 255 (T255A), which is located at the junction of intracellular loop 3 and transmembrane domain 6, reduces the hMCHR1 cell surface expression level to 20% of that observed for the wild-type receptor. Most of these mutant receptors are located intracellularly, as opposed to the wild-type receptor, which is located primarily on the cell surface. Immunoprecipitation experiments show that hMCHR1-T255A has reduced glycosylation compared with the wild-type receptor and is associated with the chaperone protein, calnexin, and it colocalizes in the endoplasmic reticulum with KDEL-containing proteins. We also demonstrate that a cell-permeable small molecule antagonist of hMCHR1 can function as a pharmacological chaperone to restore cell surface expression of this and other MCHR1 mutants to wild-type levels. Once rescued, the T255A mutant couples to Gq proteins as efficiently as the wild-type receptor. These data suggest that this single mutation produces an hMCHR1 that folds incorrectly, resulting in its retention in the endoplasmic reticulum, but once rescued to the cell surface can still function normally.
Formation of E-Cadherin-Mediated Cell-Cell Adhesion Activates Akt and Mitogen Activated Protein Kinase via Phosphatidylinositol 3 Kinase and Ligand-Independent Activation of Epidermal Growth Factor Receptor in Ovarian Cancer Cells
Authors: Reddy Pradeep , Liu Lian , Ren Chong , Lindgren Peter , Boman Karin , Shen Yan , Lundin Eva , Ottander Ulrika , Rytinki Miia , Liu Kui
Published: June 2005

E-cadherin is a well characterized adhesion molecule that plays a major role in epithelial cell adhesion. Based on findings that expression of E-cadherin is frequently lost in human epithelial cancers, it has been implicated as a tumor suppressor in carcinogenesis of most human epithelial cancers. However, in ovarian cancer development, our data from the current study showed that E-cadherin expression is uniquely elevated in 86.5% of benign, borderline, and malignant ovarian carcinomas irrespective of the degree of differentiation, whereas normal ovarian samples do not express E-cadherin. Thus, we hypothesize that E-cadherin may play a distinct role in the development of ovarian epithelial cancers. Using an E-cadherin-expressing ovarian cancer cell line OVCAR-3, we have demonstrated for the first time that the establishment of E-cadherin mediated cell-cell adhesions leads to the activation of Akt and MAPK. Akt activation is mediated through the activation of phosphatidylinositol 3 kinase, and both Akt and MAPK activation are mediated by an E-cadherin adhesion-induced ligand-independent activation of epidermal growth factor receptor. We have also demonstrated that suppression of E-cadherin function leads to retarded cell proliferation and reduced viability. We therefore suggest that the concurrent formation of E-cadherin adhesion and activation of downstream proliferation signals may enhance the proliferation and survival of ovarian cancer cells. Our data partly explain why E-cadherin is always expressed during ovarian tumor development and progression.
Formation of the head organizer in hydra involves the canonical Wnt pathway
Authors: Broun Mariya , Gee Lydia , Reinhardt Beate , Bode Hans R.
Published: June 2005

Stabilization of β-catenin by inhibiting the activity of glycogen synthase kinase-3β has been shown to initiate axis formation or axial patterning processes in many bilaterians. In hydra, the head organizer is located in the hypostome, the apical portion of the head. Treatment of hydra with alsterpaullone, a specific inhibitor of glycogen synthase kinase-3β,results in the body column acquiring characteristics of the head organizer, as measured by transplantation experiments, and by the expression of genes associated with the head organizer. Hence, the role of the canonical Wnt pathway for the initiation of axis formation was established early in metazoan evolution.
Notch signaling functions as a binary switch for the determination of glandular and luminal fates of endodermal epithelium during chicken stomach development
Authors: Matsuda Yoshimasa , Wakamatsu Yoshio , Kohyama Jun , Okano Hideyuki , Fukuda Kimiko , Yasugi Sadao
Published: June 2005

During development of the chicken proventriculus (glandular stomach), gut endoderm differentiates into glandular and luminal epithelium. We found that Delta1-expressing cells, undifferentiated cells and Notch-activated cells colocalize within the endodermal epithelium during early gland formation. Inhibition of Notch signaling using Numb or dominant-negative form of Su(H) resulted in a luminal differentiation, while forced activation of Notch signaling promoted the specification of immature glandular cells, but prevented the subsequent differentiation and the invagination of the glands. These results suggest that Delta1-mediated Notch signaling among endodermal cells functions as a binary switch for determination of glandular and luminal fates, and regulates patterned differentiation of glands in the chicken proventriculus.
A novel G protein-coupled receptor, related to GPR4, is required for assembly of the cortical actin skeleton in earlyXenopusembryos
Authors: Tao Qinghua , Lloyd Brett , Lang Stephanie , Houston Douglas , Zorn Aaron , Wylie Chris
Published: June 2005

As the fertilized Xenopus egg undergoes sequential cell divisions to form a blastula, each cell develops a network of cortical actin that provides shape and skeletal support for the whole embryo. Disruption of this network causes loss of shape and rigidity of the embryo, and disrupts gastrulation movements. We previously showed that lysophosphatidic acid (LPA)signaling controls the change in cortical actin density that occurs at different stages of the cell cycle. Here, we use a gain-of-function screen,using an egg cDNA expression library, to identify an orphan G protein-coupled cell-surface receptor (XFlop) that controls the overall amount of cortical F-actin. Overexpression of XFlop increases the amount of cortical actin, as well as embryo rigidity and wound healing, whereas depletion of maternal XFlop mRNA does the reverse. Both overexpression and depletion of XFlop perturb gastrulation movements. Reciprocal rescue experiments, and comparison of the effects of their depletion in early embryos, show that the XLPA and XFlop signaling pathways play independent roles in cortical actin assembly, and thus that multiple signaling pathways control the actin skeleton in the blastula.
Hippocampal and visuospatial learning defects in mice with a deletion of frizzled 9, a gene in the Williams syndrome deletion interval
Authors: Zhao Chunjie , Avilés Carmen , Abel Regina A. , Almli C. Robert , McQuillen Patrick , Pleasure Samuel J.
Published: June 2005

Wnt signaling regulates hippocampal development but little is known about the functions of specific Wnt receptors in this structure. Frizzled 9 is selectively expressed in the hippocampus and is one of about 20 genes typically deleted in Williams syndrome. Since Williams syndrome is associated with severe visuospatial processing defects, we generated a targeted null allele for frizzled 9 to examine its role in hippocampal development. Frizzled 9-null mice had generally normal gross anatomical hippocampal organization but showed large increases in apoptotic cell death in the developing dentate gyrus. This increase in programmed cell death commenced with the onset of dentate gyrus development and persisted into the first postnatal week of life. There was also a perhaps compensatory increase in the number of dividing precursors in the dentate gyrus, which may have been a compensatory response to the increased cell death. These changes in the mutants resulted in a moderate decrease in the number of adult dentate granule cells in null mice and an increase in the number of hilar mossy cells. Heterozygous mice (the same frizzled 9 genotype as Williams syndrome patients) were intermediate between wild type and null mice for all developmental neuronanatomic defects. All mice with a mutant allele had diminished seizure thresholds, and frizzled 9 null mice had severe deficits on tests of visuospatial learning/memory. We conclude that frizzled 9 is a critical determinant of hippocampal development and is very likely to be a contributing factor to the neurodevelopmental and behavioral phenotype of patients with Williams syndrome.