Interobserver agreement and diagnostic performance of individual MRI criteria for diagnosis of placental adhesion disorders.

AIM: To assess the diagnostic accuracy of several criteria for the diagnosis of placental adhesion disorder (PAD) on magnetic resonance imaging (MRI) and to assess interobserver agreement and reader accuracy based on years of interpretive experience. MATERIALS AND METHODS: Blinded evaluation of the placental MRI studies of 28 randomly selected women, 18 with PADs and 10 without PADs, was undertaken by three radiologists with 10, 5, and 2 years' experience in placental MRI interpretation. The presence of placenta praevia, dark intraplacental bands, heterogeneity, uterine bulging, "shaggy dog" appearance of the uterine serosa, subjective impression of extraplacental invasion, and dark intraplacental bands on diffusion-weighted imaging were assessed. Placental histology was reviewed blinded to the original reports and to MRI interpretation and this, along with clinical information at the time of delivery, formed the reference standard. RESULTS: Dark intraplacental bands on T2-weighted imaging were the most sensitive and specific as well as the most agreed upon (kappa=0.7) criterion for PAD for the three readers. Assessment of uterine bulging (kappa=0.42) and placental heterogeneity (kappa=0.48) did not improve diagnostic accuracy. DWI improved sensitivity but decreased specificity for the least experienced reader and did not change sensitivity or specificity for the more experienced readers. CONCLUSION: Assessment of the placenta for dark bands is the most sensitive, specific, and reproducible criterion for diagnosis of PADs using MRI.

Histologic changes in traumatized skeletal muscle exposed to seawater: a canine cadaver study.

Wounds were created by incision in skeletal muscle of 2 mixed-breed canine cadavers at multiple time points from 0.5 to 74.5 hours postmortem and were exposed to artificial seawater (35 parts per thousand), 0.9% saline (8 parts per thousand), or freshwater for 24 hours before fixation for histology. Discoid and segmental disintegration of myofibers deep to the severed edges was observed in injuries inflicted within 6.5 hours of death and exposed to 0.9% saline and seawater and was not observed in injuries made at later time points or in other treatments. Exposure to artificial seawater had pronounced effects on histomorphology that markedly diminished with increasing postmortem wounding interval. In a third cadaver, these changes were shown to be detectable with confidence following up to 10 days of submergence in seawater at 22.2°C despite decomposition. These findings are important for evaluation of skeletal muscle injuries that are exposed to seawater, such as those occurring in marine animals, and may assist in recognizing wounds inflicted either antemortem or within the supravital period.

Post-transcriptional gene regulation by HuR promotes a more tumorigenic phenotype.

In a breast tumor xenograft model, the MCT-1 oncogene increases the in vivo tumorgenicity of MCF7 cells by promoting angiogenesis and inhibiting apoptosis. Increases in the tumor microvascular density are accompanied by a strong reduction in the levels of the angiogenesis inhibitor thrombospondin-1 (TSP1), but the mechanisms underlying this process are unknown. We show that TSP1 expression is controlled, at least in part, by post-transcriptional events. Using RNA interference to knock down the expression of the RNA-binding protein HuR in MCF7 cells as well as HuR overexpression, we demonstrate that HuR plays an important role in translation of the TSP1 mRNA. Furthermore, employing the RIP-Chip assay yielded 595 transcripts with significantly altered binding to HuR in the more tumorigenic breast cancer clones compared with the weakly tumorigenic clones. These mRNAs clustered in several pathways implicated in the transformed phenotype, such as the RAS pathway (involved in mitogenesis), the PI3K pathway (evasion of apoptosis) and pathways mediating angiogenesis and the cellular response to hypoxia. These findings demonstrate for the first time that global changes in HuR-bound mRNAs are implicated in the evolution to a more tumorigenic phenotype in an in vivo tumor model and underscore the role of global mRNA-protein interactions toward tumor progression.

Classification and localization of acetabular labral tears.

OBJECTIVE: The purpose of this study was to compare the findings on hip MR arthrography (MRA) with the published MRA and arthroscopic classifications of hip labral tears and to evaluate a clock-face method for localizing hip labral tears. DESIGN/PATIENTS: We retrospectively reviewed 65 hip MRA studies with correlative hip arthroscopies. Each labrum was evaluated on MRA using the classification system of Czerny and an MRA modification of the Lage arthroscopic classification. In addition, each tear was localized on MRA by using a clock-face description where 6 o'clock was the transverse ligament and 3 o'clock was anterior. These MRA findings were then correlated with the arthroscopic findings using the clock-face method of localization and the Lage arthroscopic classification of labral tears. RESULTS: At MRA, there were 42 Czerny grade 2 and 23 grade 3 labral tears and 22 MRA Lage type 1, 11 type 2, 22 type 3 and 10 type 4 tears. At arthroscopy, there were 10 Lage type 1 flap tears, 20 Lage type 2 fibrillated tears, 18 Lage type 3 longitudinal peripheral tears and 17 Lage type 4 unstable tears. The Czerny MRA classification and the modified MRA Lage classification had borderline correlation with the arthroscopic Lage classification. Localization of the tears using a clock-face description was within 1 o'clock of the arthroscopic localization of the tears in 85% of the patients. CONCLUSIONS: The Lage classification, which is the only published arthroscopic classification system for hip labral tears, does not correlate well with the Czerny MRA or an MRA modification of the Lage classification. Using a clock-face description to localize tears provides a way to accurately localize a labral tear and define its extent.

Are mental health problems associated with use of Accident and Emergency and health-related harm?

BACKGROUND: Previous findings indicate that mental health problems are common in Emergency departments; however, there are few studies of the extent of health-related problems and emergency service use in mental health populations as a whole. METHODS: Record linkage methods were used to map the association between mental health, age, gender, and health-related harm across total health and mental health care populations in one geographical area, over three years. By examining patterns of health-related harm, an accurate profile of mentally ill Emergency patients was generated enabling identification of factors that increased vulnerability to harm. RESULTS: Of the total population of 625 964 individuals, 10.7% contacted Accident and Emergency (A&E) over three years, this proportion rose to 28.6% among the total secondary care mental health population. Young men and older women were more likely to contact A&E, both overall and within mental health populations and were also more likely to be frequent attendees at A&E. Four distinct groups (typologies) of mental health patients attending A&E emerged: young, male frequent attendees with self-inflicted and other traumatic injuries; young females also presenting with self-harm; older patients with multiple medical conditions; and very old patients with cardiac conditions and fractures. CONCLUSION: The study indicates increased A+E service use and unmet health-related need within a total mental health population. It identifies specific 'care populations' particularly vulnerable to accidents and self-harm and highlights the need for targeted services for mentally ill groups who may not access traditional health and social care services effectively.

Biological clocks and the coordination theory of RNA operons and regulons.

One of the regulatory models of circadian rhythms involves the oscillation of transcription and translation. Although transcription factors have been widely examined during circadian processes, posttranscriptional mechanisms are less well-studied. Several laboratories have used microarrays to detect changes in mRNA expression throughout the circadian cycle and have found that mRNAs encoding the RNA-binding proteins (RBPs) nocturnin and butyrate response factor (BRF1) undergo rhythmic changes. Nocturnin is a deadenylation enzyme that removes poly(A) from the 3' ends of mRNAs, whereas BRF1 destabilizes mRNAs encoding early response gene (ERG) transcripts that contain AU-rich sequences in their 3'-untranslated regions (UTRs). Moroni and coworkers proposed that BRF1 functions as an oscillating posttranscriptional RNA operon (PTRO) that diurnally degrades ERG transcripts in peripheral organs (Keene and Tenenbaum 2002; Benjamin et al. 2006). The PTRO model posits that mRNAs can be members of one or more discrete functionally related subsets of mRNAs as determined by cis elements in mRNA and trans-acting RBPs or microRNAs that collectively recognize these cis elements (Keene 2007). This chapter describes the basis of posttranscriptional coordination by RNA operons and their potential for horizontal transfer among cells and discusses the potential for RBPs and microRNAs to participate in coordinating circadian rhythms and other biological clocks.

Gender differences in older patient populations: a case linkage study of community health, mental health, and social services in the United Kingdom.

We identify gender differences in older health and social care populations by comparing the total population of older people with the total population of women and the total population of older women, respectively. We combine anonymised data across community health (CH; N = 82,751), mental health (MH; N = 19,029), and social care service (SC; N = 19,461) populations in one UK county (N = 496,863) over 3 years. Approximately two thirds of older care populations were female. In both single- and dual-agency care populations a profile emerged of older patients, female patients and older female patients, this profile varied across different diagnostic and care groups.

Age and gender differences in health service utilization.

BACKGROUND: This study of age and gender profiles of health care populations fills a gap in the research literature by providing a population study of both single health agency and inter-agency 'Shared Care' populations. METHODS: It combines anonymous data to link individual cases across Community Health (N = 82 751), Mental Health (N = 19 029) and Social Services (N = 19 461) populations in one county Health Authority (N = 646 239) over 3 years. It compares age and gender characteristics of single care populations and overlapping inter-agency 'Shared Care'populations. RESULTS: Approximately two-thirds of all care populations were female compared to half (513.1) in the general Health Authority population. These differences were accentuated for almost all inter-agency 'Shared Care' populations, where, whilst a younger care profile emerged for mental health and social services dual agency clients, for other shared populations a distinct care profile emerged of greater proportions of older, female and older female patients. Gender differences were also apparent for different care groups within a total Community Health care population. Whilst females made much more use of services overall, in Community Health, older males were more likely to receive rehabilitative support services. CONCLUSION: Age and gender profiles of health care agency and inter-agency populations clarify service use patterns and identify high proportions of women in health and social care populations, particularly in older care populations. This type of care population analysis could inform single agency and inter-agency shared care planning and commissioning.

A cross sectional study of assessed need and multiple service use among a self harm population: informing the development of inter-agency integrated care.

PURPOSE: To examine assessed need and wider health and social care service contact for a total Deliberate Self Harm (DSH) population in the UK. METHODS: The study first recorded assessed needs and referrals for this population, then used a new method of identifying and describing all other agency contacts for this population by combining the total anonymised DSH population data with total mental health, health and social care agency populations for one geographical area. RESULTS: For a DSH unit population of 427, half (53%) were assessed with mental health and 18% with drug or alcohol problems; two thirds were referred to appropriate services. Wider service contact for a total DSH population (n=2,205 over three years) confirmed that 53% had contacted mental health (compared to 2.9% of the geographical area population (n=646,239) and 7.4% of the total hospital Emergency population (n=91,911). The DSH population was three times more likely to contact social care agencies (21.1%: 7.2%) and ten times more likely to attend drug (7.3%: 0.7%) and alcohol agencies (8.8%: 0.8%) CONCLUSIONS: This new method described the wider service use of one vulnerable shared care population, it is suggested that the method could be used to inform the development of integrated care initiatives in different areas.

Loss of serotonin 5-HT2A receptors in the postmortem temporal cortex correlates with rate of cognitive decline in Alzheimer's disease.

RATIONALE: Previous studies have demonstrated reductions of serotonin 5-HT 2A receptors in the neocortex of Alzheimer's disease (AD) patients. However, it is unclear whether such losses play a role in the cognitive decline of AD. OBJECTIVES: To correlate neocortical 5-HT 2A receptor alterations with cognitive decline in AD. METHODS: Postmortem frontal and temporal cortical 5-HT 2A receptors were measured by [3H]ketanserin binding in aged controls as well as in a cohort of AD patients who had been longitudinally assessed for cognitive decline and behavioral symptoms. RESULTS: 5-HT 2A receptor densities in both regions were reduced in severely demented AD patients compared to age-matched controls. In the temporal cortex, this reduction also correlated with the rate of decline of Mini-Mental State Examination (MMSE) scores. The association between 5-HT 2A receptor loss and cognitive decline was independent of the effects of choline acetyltransferase (ChAT) activity and presence of behavioral symptoms. CONCLUSIONS: Our data suggest that loss of neocortical 5-HT 2A receptors may predict for faster cognitive decline in AD, and point to serotomimetics as potentially useful adjuvants to cholinergic replacement therapies.

Search for organising principles: understanding in systems biology.

Due in large measure to the explosive progress in molecular biology, biology has become arguably the most exciting scientific field. The first half of the 21st century is sometimes referred to as the 'era of biology', analogous to the first half of the 20th century, which was considered to be the 'era of physics'. Yet, biology is facing a crisis--or is it an opportunity--reminiscent of the state of biology in pre-double-helix time. The principal challenge facing systems biology is complexity. According to Hood, 'Systems biology defines and analyses the interrelationships of all of the elements in a functioning system in order to understand how the system works.' With 30000+ genes in the human genome the study of all relationships simultaneously becomes a formidably complex problem. Hanahan and Weinberg raised the question as to whether progress will consist of 'adding further layers of complexity to a scientific literature that is already complex almost beyond measure' or whether the progress will lead to a 'science with a conceptual structure and logical coherence that rivals that of chemistry or physics.' At the core of the challenge is the need for a new approach, a shift from reductionism to a holistic perspective. However, more than just a pronouncement of a new approach is needed. We suggest that what is needed is to provide a conceptual framework for systems biology research. We propose that the concept of a complex system, i.e. a system of systems as defined in mathematical general systems theory (MGST), is central to provide such a framework. We further argue that for a deeper understanding in systems biology investigations should go beyond building numerical mathematical or computer models--important as they are. Biological phenomena cannot be predicted with the level of numerical precision as in classical physics. Explanations in terms of how the categories of systems are organised to function in ever changing conditions are more revealing. Non-numerical mathematical tools are appropriate for the task. Such a categorical perspective led us to propose that the core of understanding in systems biology depends on the search for organising principles rather than solely on construction of predictive descriptions (i.e. models) that exactly outline the evolution of systems in space and time. The search for organising principles requires an identification/discovery of new concepts and hypotheses. Some of them, such as coordination motifs for transcriptional regulatory networks and bounded autonomy of levccels in a hierarchy, are outlined in this article. Experimental designs are outlined to help verify the applicability of the interaction balance principle of coordination to transcriptional and posttranscriptional networks.

Mental health patients in criminal justice populations: needs, treatment and criminal behaviour.

BACKGROUND: Government policy requires that health and social care agencies work more closely together and in partnership with the criminal justice system. There is a well-established relationship between crime and mental disorder. METHOD: The Tracking Project provides for the first time in England the means of collating and analysing data on mental disorder (defined as receiving secondary care as patients of a Mental Health Trust) and crime (defined as all those charged with an offence). Data were collected over a three-year period for all individuals who had contact with the criminal justice system and mental health services in an English county. RESULTS: In a county population of 800,400, some 30,329 were offenders. More than a third had used a health or social care service during the three-year period; 8.0% were mentally disordered. Those offenders aged 25-64 and who contacted the police more than once were significantly more likely to be mentally disordered. Type of offence was also a relevant variable. The probation service showed broadly similar results. DISCUSSION: The research has provided for the first time substantive quantitative evidence of the relationship between crime and mental disorder. The results can be used as the basis for further work to target assessment and risk reduction measures at those most at risk.

Estimating the relationship between disease progression and cost of care in dementia.

BACKGROUND: Previous studies have shown a positive relationship between disease severity and cost. AIMS: To explore the factors affecting time to institutionalisation and estimate the relationship between the costs of care and disease progression. METHOD: Retrospective analysis of a longitudinal data-set for a cohort of 100 patients diagnosed with Alzheimer's disease or vascular dementia. RESULTS: Changes in both Mini-Mental State Examination (MMSE) and Barthel scores have independent and significant marginal effects on costs. Each one-point decline in the MMSE score is associated with a pound sterling 56 increase in the four-monthly costs, whereas each one-point fall in the Barthel index is associated with a pound sterling 586 increase in costs. CONCLUSIONS: It may be inappropriate for economic models of disease progression in dementia to be based solely on measures of cognitive change. MMSE and the Barthel index are independent significant predictors of time to institutionalisation and cost of care, but changes in the Barthel index are particularly important in predicting costs outside institutional care.

Microarray identification of FMRP-associated brain mRNAs and altered mRNA translational profiles in fragile X syndrome.

Fragile X syndrome results from the absence of the RNA binding FMR protein. Here, mRNA was coimmunoprecipitated with the FMRP ribonucleoprotein complex and used to interrogate microarrays. We identified 432 associated mRNAs from mouse brain. Quantitative RT-PCR confirmed some to be >60-fold enriched in the immunoprecipitant. In parallel studies, mRNAs from polyribosomes of fragile X cells were used to probe microarrays. Despite equivalent cytoplasmic abundance, 251 mRNAs had an abnormal polyribosome profile in the absence of FMRP. Although this represents <2% of the total messages, 50% of the coimmunoprecipitated mRNAs with expressed human orthologs were found in this group. Nearly 70% of those transcripts found in both studies contain a G quartet structure, demonstrated as an in vitro FMRP target. We conclude that translational dysregulation of mRNAs normally associated with FMRP may be the proximal cause of fragile X syndrome, and we identify candidate genes relevant to this phenotype.

Synaptic pathology in prefrontal cortex is present only with severe dementia in Alzheimer disease.

Synaptic pathology is proposed to be integral to the clinical expression of Alzheimer disease (AD). Most studies have assessed only the vesicle protein synaptophysin as a measure of synaptic integrity. The interrelationships of synaptophysin, other presynaptic proteins, the cholinergic system, and severity of dementia in AD remain unclear. We studied the presynaptic proteins synaptophysin, syntaxin and SNAP-25, along with choline acetyltransferase (ChAT) activity in prefrontal cortex (BA 46) samples from 18 subjects with AD and 16 controls. Mean values of presynaptic protein immunoreactivities were significantly reduced, by 21%-28%, and ChAT activity was reduced by 41% in the AD groups. Synaptic protein immunoreactivity and ChAT activity were correlated with Mini-Mental State Examination scores obtained 1 yr prior to death. When AD cases were subgrouped into mild/moderate and severe illness at time of death, all differences in presynaptic proteins and ChAT activity were significant between controls and severe cases. However, no significant differences were detected in BA 46 between controls and mild/moderate cases. Considerable synaptic reserve or plasticity remains in BA 46 until the late stages of AD. Synaptophysin and ChAT appear to be more vulnerable in severe AD than are syntaxin or SNAP-25.

Death and dementia.

OBJECTIVE: To investigate the last phase of dementia and the causes of death; comparing autopsy and death certificate diagnoses. DESIGN: Prospective, 11-year, longitudinal study of behavioural and psychological changes in dementia, with autopsy follow-up. SETTING: Participants with dementia, living at home with a carer. All lived in Oxfordshire, UK. PARTICIPANTS: Ninety-one people with dementia (Alzheimer's disease and/or vascular dementia) who died during the course of the study. MEASURES: At four-monthly intervals, carers were interviewed about the participants' behaviour using the Present Behavioural Examination. Participants were also assessed cognitively. Causes of death were established from death certificates and, where possible, from post-mortem examination. RESULTS: The main immediate cause of death recorded at autopsy was pneumonia (57%), followed by cardiovascular disease (16%) and pulmonary embolus (14%). This agreed with the immediate cause of death on 53% of death certificates. Pulmonary embolism and bronchopneumonia were under-reported on death certificates. Dementia was mentioned on 73% of death certificates. The dementing illness lasted for a mean of 8.5 years with 58% dying in a debilitated state associated with severe dementia. In the period before death, 35% were unable to walk, 58% were hypophagic, 73% were incontinent of urine, 21% incontinent of faeces and 76% entered an institution permanently for a mean period of 18 months. CONCLUSION: Family and professional carers of people with dementia can be given some information about prognosis to help them plan for the likely outcome of dementia.

Psychosis of Alzheimer's disease is associated with elevated muscarinic M2 binding in the cortex.

OBJECTIVES: Results from recent drug trials suggest a role for the cholinergic system in the manifestation of neuropsychiatric symptoms in AD. To date, the status of muscarinic acetylcholine receptor subtypes in AD in relation to accompanying behavioral disturbances is unknown. This study aimed to measure alterations of muscarinic M(1) and M(2) receptor binding in the frontal and temporal cortex of AD and to correlate the neurochemical findings with clinical features. METHODS: The cognitive and behavioral features of 26 patients with AD were assessed prospectively using standardized tests. Together with 14 matched controls, the status of muscarinic M(1) and M(2) receptors in the postmortem frontal and temporal cortex of these patients were measured by radioligand binding assays and were correlated with clinical data. RESULTS: Compared with controls, M(2) receptor density was reduced only in the frontal cortex of AD, whereas M(1) was unaffected. Within the AD group, the neurochemical variables were not affected by demographic factors, disease severity, or cognition. Instead, M(2) receptor density was increased in the frontal and temporal cortex of patients with AD with psychotic symptoms compared with those without these symptoms. CONCLUSIONS: This study suggests a role for M(2) receptors in the psychosis of AD and may provide the rationale for treatment of behaviorally perturbed patients with AD with cholinomimetics and M(2) antagonists.

Shared patients: multiple health and social care contact.

The paper describes results from the 'Tracking Project', a new method for examining agency overlap, repeat service use and shared clients/patients amongst social and health care agencies in the community. This is the first project in this country to combine total population databases from a range of social, health care and criminal justice agencies to give a multidisciplinary database for one county (n = 97,162 cases), through standardised anonymisation of agency databases, using SOUNDEX, a software programme. A range of 20 community social and health care agencies were shown to have a large overlap with each other in a two-year period, indicating high proportions of shared patients/clients. Accident and Emergency is used as an example of major overlap: 16.2% (n = 39,992) of persons who attended a community agency had attended Accident and Emergency as compared to 8.2% (n = 775,000) of the total population of the county. Of these, 96% who had attended seven or more different community agencies had also attended Accident and Emergency. Further statistical analysis of Accident and Emergency attendance as a characteristic of community agency populations (n = 39,992) revealed that increasing frequency of attendance at Accident and Emergency was very strongly associated with increasing use of other services. That is, the patients that repeatedly attend Accident and Emergency are much more likely to attend more other agencies, indicating the possibility that they share more problematic or difficult patients. Research questions arising from these data are discussed and future research methods suggested in order to derive predictors from the database and develop screening instruments to identify multiple agency attenders for targeting or multidisciplinary working. It is suggested that Accident and Emergency attendance might serve as an important predictor of multiple agency attendance.

Wandering in dementia: a longitudinal study.

OBJECTIVE: This article analyzes the natural history of wandering behavior throughout the course of dementia. DESIGN: Prospective, 10-year, longitudinal study of wandering behavior in dementia, with autopsy follow-up. SETTING: Participants with dementia, living at home with a carer. All lived in Oxfordshire, UK. PARTICIPANTS: Eighty-six people with dementia who were living at home with a carer and who were able to walk unaided at entry to study. MEASURES: At 4-monthly intervals, the carers were interviewed using the Present Behavioural Examination to assess wandering behavior in detail; participants with dementia were assessed cognitively. Nine types of "wandering" behavior were distinguished. RESULTS: Changes in wandering behavior were not generally related to gender, age, or time since onset of dementia. Onset of different types of wandering behavior showed some relationship with cognitive state. Various forms of increased walking first appeared during moderate dementia, each type typically persisting for 1 to 2 years. Late dementia was characterized by decreased walking and immobility. CONCLUSIONS: Wandering behavior in dementia can cause great problems for carers. There are different causes for such changes, some of which are related to cognitive ability, for example increased confusion results in ineffectual "pottering" and getting lost. Increased walking at night corresponds with disruption of diurnal rhythm.

Cardiopulmonary support for emergent innominate artery repair complicating tracheal surgery.

Innominate artery rupture is a rare, but usually fatal, complication of tracheal stenosis. Although prevention is key, prompt, appropriate intervention can be life saving. Hemorrhage and airway must simultaneously be controlled. Most deaths occur from exsanguination with adequate ventilation before surgical repair can be effected. In the ideal situation, the event would occur in the operating room. We report on just such a case with concomitant respiratory failure requiring cardiopulmonary support in order to accomplish definitive therapy.