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Domestication of the helmeted guinea fowl (HGF; Numida meleagris) in Africa remains elusive. Here we report a high-quality de novo genome assembly for domestic HGF generated by long- and short-reads sequencing together with optical and chromatin interaction mapping. Using this assembly as the reference, we performed population genomic analyses for newly sequenced whole-genomes for 129 birds from Africa, Asia, and Europe, including domestic animals (n = 89), wild progenitors (n = 34), and their closely related wild species (n = 6). Our results reveal domestication of HGF in West Africa around 1,300-5,500 years ago. Scanning for selective signals characterized the functional genes in behavior and locomotion changes involved in domestication of HGF. The pleiotropy and linkage in genes affecting plumage color and fertility were revealed in the recent breeding of Italian domestic HGF. In addition to presenting a missing piece to the jigsaw puzzle of domestication in poultry, our study provides valuable genetic resources for researchers and breeders to improve production in this species.

Background. Estimates for fish and shellfish intake are used to inform communities and healthcare systems about potential health risks and benefits for individuals, communities, and vulnerable populations. A dietary assessment instrument was designed for use in populations of high-end consumers of seafood to examine intake of finfish, shrimp, oysters, and blue crab in coastal communities across the Gulf of Mexico. Objective. To validate the reliability of a novel food frequency questionnaire (FFQ) for seafood intake. Design. Test-retest reliability of the FFQ, which included a species-specific photographic portion guide, was evaluated by the inperson administration and readministration of the instrument with each participant by the same interviewer. Responses from coastal and noncoastal participants were compared to discern FFQ reliability in heterogeneous samples. Participants/setting. A convenience sample of 27 coastal participants from Cedar Key, Steinhatchee, and Apalachicola, Florida, reported data for 101 household members; and 15 noncoastal participants from Gainesville, Florida, reported for 42 household members. Analysis. Repeated measures from the FFQ were evaluated using correlation concordance for continuous variables (age, weight, and height) and kappa coefficient for categorical variables (type, amount, and frequency of seafood consumed). Results. Concordance correlation coefficient (1.00) and kappa coefficient (r = 0.73 to 1.00) for yearly and seasonal seafood consumption indicated substantial to almost perfect reproducibility, i.e., participants provided responses that were reproducible. Test-retest agreement was highest for coastal participants who consumed more seafood, as compared to occasional, noncoastal consumers, based on the intergroup comparison of kappa coefficients for yearly and seasonal seafood consumption (r = 0.69 to 0.99). Conclusions. The seafood FFQ instrument evaluated in this study, included as a supplement to this report, used in tandem with a photographic portion guide, provides a utilitarian tool for assessing fish, shrimp, oyster, and blue crab intake dynamics in adult and youth populations drawn from coastal communities.

The diagnoses of serious psychiatric illnesses, such as schizophrenia, schizoaffective disorder, and bipolar disorder, rely on the subjective recall and interpretation of often overlapping symptoms, and are not based on the objective pathophysiology of the illnesses. The subjectivity of symptom reporting and interpretation contributes to the delay of accurate diagnoses and limits effective treatment of these illnesses. Proteomics, the study of the types and quantities of proteins an organism produces, may offer an objective biological approach to psychiatric diagnosis. For this pilot study, we used the Myriad RBM Discovery Map 250+ platform to quantify 205 serum proteins in subjects with schizophrenia (n=26), schizoaffective disorder (n=20), bipolar disorder (n=16), and healthy controls with no psychiatric illness (n=23). Fifty-seven analytes that differed significantly between groups were used for multivariate modeling with linear discriminant analysis (LDA). Diagnoses generated from these models were compared to SCID-generated clinical diagnoses to determine whether the proteomic markers: 1) distinguished the three disorders from controls, and 2) distinguished between the three disorders. We found that a series of binary classification models including 8-12 analytes produced separation between all subjects and controls, and between each diagnostic group and controls. There was a high degree of accuracy in the separations, with training areas-under-the-curve (AUC) of 0.94-1.0, and cross-validation AUC of 0.94-0.95. Models with 7-14 analytes produced separation between the diagnostic groups, though less robustly, with training AUC of 0.72-1.0 and validation AUC of 0.69-0.89. While based on a small sample size, not adjusted for medication state, these preliminary results support the potential of proteomics as a diagnostic aid in psychiatry. The separation of schizophrenia, schizoaffective disorder, and bipolar disorder suggests that further work in this area is warranted.

Background Cardiac injury is a significant cause of death in patients with traumatic injuries. The Oklahoma Trauma Registry collects data from acute care hospitals in Oklahoma. This study investigated the trends and outcomes of traumatic cardiac injury in Oklahoma over a 10-year period. Methods The Oklahoma Trauma Registry tracks patients with major severity and one of the following criteria: hospital stay 48 hours or longer, death on arrival or in the hospital, hospital transfer, intensive care unit admission, or surgery. Cardiac injuries were identified from data acquired 2005 to 2014. Characteristics, mechanisms of injury, associated injuries, and outcomes were analyzed. Results were further divided into blunt vs penetrating injuries and operative vs nonoperative management. Results Of 107,549 patients, 426 patients suffered cardiac injury, and 160 patients suffered penetrating trauma. Commonly associated injuries were rib fractures, pneumothorax, hemothorax, and intraabdominal injuries. Of blunt cardiac injuries, 26.7% had spinal fractures. Operative management occurred in 16.9%. Overall mortality rate was 35.7% (51.9% in penetrating and 26.3% in blunt injuries). Mortality was higher for patients who had operative management but was similar in penetrating and blunt cardiac injury. Over 10 years, the percentage of cardiac injury decreased. However, mortality in patients who suffered a cardiac injury increased, correlating with an increase in proportion of penetrating cardiac injury. Conclusions Traumatic cardiac injury, particularly penetrating injury, continues to be a significant source of mortality. Analysis of state-base trauma registries can identify trends in causes of injury and death, serving as a reference point for quality improvement, therapeutic triage, and preventative action plans.

BackgroundMedication organisation devices (MODs) provide compartments for a patient’s medication to be organised into the days of the week and the recommended times the medication should be taken.AimTo define the optimal trial design for testing the clinical effectiveness and cost-effectiveness of MODs.DesignThe feasibility study comprised a systematic review and focus groups to inform a randomised controlled trial (RCT) design. The resulting features were tested on a small scale, using a 2 × 2 factorial design to compare MODs with usual packaging and to compare weekly with monthly supply. The study design was then evaluated.SettingPotential participants were identified by medical practices.ParticipantsAged over 75 years, prescribed at least three solid oral dosage form medications, unintentionally non-adherent and self-medicating. Participants were excluded if deemed by their health-care team to be unsuitable.InterventionsOne of three MODs widely used in routine clinical practice supplied either weekly or monthly.ObjectivesTo identify the most effective method of participant recruitment, to estimate the prevalence of intentional and unintentional non-adherence in an older population, to provide a point estimate of the effect size of MODs relative to usual care and to determine the feasibility and acceptability of trial participation.MethodsThe systematic review included MOD studies of any design reporting medication adherence, health and social outcomes, resource utilisation or dispensing or administration errors. Focus groups with patients, carers and health-care professionals supplemented the systematic review to inform the RCT design. The resulting design was implemented and then evaluated through questionnaires and group discussions with participants and health-care professionals involved in trial delivery.ResultsStudies on MODs are largely of poor quality. The relationship between adherence and health outcomes is unclear. Of the limited studies reporting health outcomes, some reported a positive relationship while some reported increased hospitalisations associated with MODs. The pre-trial focus groups endorsed the planned study design, but suggested a minimum recruitment age of 50–60 years. A total of 35.4% of patients completing the baseline questionnaire were excluded because they already used a MOD. Active recruitment yielded a higher consent rate, but passive recruitment was more cost-effective. The prevalence of intentional non-adherence was 24.7% [n = 71, 95% confidence interval (CI) 19.7% to 29.6%] of participants. Of the remaining 76 participants, 46.1% (95% CI 34.8% to 57.3%) were unintentionally non-adherent. There was no indication of a difference in adherence between the study arms. Participants reported a high level of satisfaction with the design. Five adverse/serious adverse events were identified in the MOD study arms and none was identified in the control arms. There was no discernible difference in health economic outcomes between the four study arms; the mean intervention cost was £20 per month greater for MOD monthly relative to usual supply monthly.ConclusionsMOD provision to unintentionally non-adherent older people may cause medication-related adverse events. The primary outcome for a definitive MOD trial should be health outcomes. Such a trial should recruit patients by postal invitation and recruit younger patients.Future workA study examining the association between MOD initiation and adverse effects is necessary and a strategy to safely introduce MODs should be explored. A definitive study testing the clinical effectiveness and cost-effectiveness of MODs is also required.Study registrationCurrent Controlled Trials ISRCTN 30626972 and UKCRN 12739.FundingThis project was funded by National Institute for Health Research (NIHR) Health Technology Assessment Programme and will be published in full inHealth Technology Assessment; Vol. 20, No. 50. See the NIHR Journals Library website for further project information.

Objectives: One of the most prominent features of schizophrenia is relatively lower general cognitive ability (GCA). An emerging approach to understanding the roots of variation in GCA relies on network properties of the brain. In this multi-center study, we determined global characteristics of brain networks using graph theory and related these to GCA in healthy controls and individuals with schizophrenia. Methods: Participants (N=116 controls, 80 patients with schizophrenia) were recruited from four sites. GCA was represented by the first principal component of a large battery of neurocognitive tests. Graph metrics were derived from diffusion-weighted imaging. Results: The global metrics of longer characteristic path length and reduced overall connectivity predicted lower GCA across groups, and group differences were noted for both variables. Measures of clustering, efficiency, and modularity did not differ across groups or predict GCA. Follow-up analyses investigated three topological types of connectivity—connections among high degree “rich club” nodes, “feeder” connections to these rich club nodes, and “local” connections not involving the rich club. Rich club and local connectivity predicted performance across groups. In a subsample (N=101 controls, 56 patients), a genetic measure reflecting mutation load, based on rare copy number deletions, was associated with longer characteristic path length. Conclusions: Results highlight the importance of characteristic path lengths and rich club connectivity for GCA and provide no evidence for group differences in the relationships between graph metrics and GCA. (JINS, 2016, 22, 240–249)

Borderline personality disorder (BPD) is associated with symptoms such as affect dysregulation, impaired sense of self, and self-harm behaviors. Neuroimaging research on BPD has revealed structural and functional abnormalities in specific brain regions and connections. However, little is known about the topological organizations of brain networks in BPD. We collected resting-state functional magnetic resonance imaging (fMRI) data from 20 patients with BPD and 10 healthy controls, and constructed frequency-specific functional brain networks by correlating wavelet-filtered fMRI signals from 82 cortical and subcortical regions. We employed graph-theory based complex network analysis to investigate the topological properties of the brain networks, and employed network-based statistic to identify functional dysconnections in patients. In the 0.03–0.06 Hz frequency band, compared to controls, patients with BPD showed significantly larger measures of global network topology, including the size of largest connected graph component, clustering coefficient, small-worldness, and local efficiency, indicating increased local cliquishness of the functional brain network. Compared to controls, patients showed lower nodal centrality at several hub nodes but greater centrality at several non-hub nodes in the network. Furthermore, an interconnected subnetwork in 0.03–0.06 Hz frequency band was identified that showed significantly lower connectivity in patients. The links in the subnetwork were mainly long-distance connections between regions located at different lobes; and the mean connectivity of this subnetwork was negatively correlated with the increased global topology measures. Lastly, the key network measures showed high correlations with several clinical symptom scores, and classified BPD patients against healthy controls with high accuracy based on linear discriminant analysis. The abnormal topological properties and connectivity found in this study may add new knowledge to the current understanding of functional brain networks in BPD. However, due to limitation of small sample sizes, the results of the current study should be viewed as exploratory and need to be validated on large samples in future works., Highlights • We analyzed the topology and connectivity of functional brain networks in BPD. • Patients with BPD showed altered small-world properties and network efficiency. • Patients with BPD showed altered nodal centrality at specific brain regions. • An interconnected subnetwork showed significantly lower connectivity in BPD. • Key network measures were correlated with clinical symptom scores.

Background Many pediatric surgeons have limited experience of esophageal replacement. This study reports outcomes of esophageal replacement by gastric transposition performed by a single UK-based pediatric surgeon. Methods Consecutive patients were identified who underwent esophageal replacement by gastric transposition over a 28 year period. Clinical and demographic data were collected. Weight-for-age Z-scores were calculated for esophageal atresia patients. Results Nineteen patients were identified. Indication in the majority was long-gap esophageal atresia (n = 17; 10 with tracheoesophageal fistula). At surgery, median age was 8.5 months (range 2–55); median weight was 7.4 kg (range 4.0–17.4 kg). A right-sided thoracotomy or transhiatal approach was used. Median postoperative length of stay was 17.5 days (range 7–130); median intensive care stay was three days (range 1–63). There were no deaths. Anastomotic leak rate at 30 days was 10.5% (n = 2). One patient required early stricture dilatation. Median weight-for-age Z-score increased from − 2.17 at one year of age to − 1.86, − 1.70 and − 1.93 at 5, 10 and 15 years. Conclusions Esophageal replacement by gastric transposition offers a potentially life-changing treatment; however, it is associated with significant morbidity. The majority of patients eventually achieve full oral feeding and maintenance of weight gain trajectory. A right-sided approach to the esophagus is feasible. Type of Study Treatment Study. Level of Evidence IV.

Background: Schizophrenia has a large genetic component, and the pathways from genes to illness manifestation are beginning to be identified. The Genetics of Endophenotypes of Neurofunction to Understand Schizophrenia (GENUS) Consortium aims to clarify the role of genetic variation in brain abnormalities underlying schizophrenia. This article describes the GENUS Consortium sample collection. Methods: We identified existing samples collected for schizophrenia studies consisting of patients, controls, and/or individuals at familial high-risk (FHR) for schizophrenia. Samples had single nucleotide polymorphism (SNP) array data or genomic DNA, clinical and demographic data, and neuropsychological and/or brain magnetic resonance imaging (MRI) data. Data were subjected to quality control procedures at a central site. Results: Sixteen research groups contributed data from 5199 psychosis patients, 4877 controls, and 725 FHR individuals. All participants have relevant demographic data and all patients have relevant clinical data. The sex ratio is 56.5% male and 43.5% female. Significant differences exist between diagnostic groups for premorbid and current IQ (both p < 1 × 10− 10). Data from a diversity of neuropsychological tests are available for 92% of participants, and 30% have structural MRI scans (half also have diffusion-weighted MRI scans). SNP data are available for 76% of participants. The ancestry composition is 70% European, 20% East Asian, 7% African, and 3% other. Conclusions: The Consortium is investigating the genetic contribution to brain phenotypes in a schizophrenia sample collection of > 10,000 participants. The breadth of data across clinical, genetic, neuropsychological, and MRI modalities provides an important opportunity for elucidating the genetic basis of neural processes underlying schizophrenia. We are grateful for the support of all study staff and participants. Acknowledgements for each sample are provided in the Supplementary Materials. Data processing and analyses (of the legacy data) at the central site was supported by the National Institute of Mental Health (NIMH) of the National Institutes of Health (NIH) grant number R01MH092380 to T.L.P. supporting the Genetics of Endophenotypes of Neurofunction to Understand Schizophrenia (GENUS) Consortium, and NIMH grant R21MH109819 to E.D.R. Appendix A

Stable neuropsychological deficits may provide a reliable basis for identifying etiological subtypes of schizophrenia. The aim of this study was to identify clusters of individuals with schizophrenia based on dimensions of neuropsychological performance, and to characterize their neural correlates. We acquired neuropsychological data as well as structural and functional magnetic resonance imaging from 129 patients with schizophrenia and 165 healthy controls. We derived eight cognitive dimensions and subsequently applied a cluster analysis to identify possible schizophrenia subtypes. Analyses suggested the following four cognitive clusters of schizophrenia: (1) Diminished Verbal Fluency, (2) Diminished Verbal Memory and Poor Motor Control, (3) Diminished Face Memory and Slowed Processing, and (4) Diminished Intellectual Function. The clusters were characterized by a specific pattern of structural brain changes in areas such as Wernicke's area, lingual gyrus and occipital face area, and hippocampus as well as differences in working memory-elicited neural activity in several fronto-parietal brain regions. Separable measures of cognitive function appear to provide a method for deriving cognitive subtypes meaningfully related to brain structure and function. Because the present study identified brain-based neural correlates of the cognitive clusters, the proposed groups of individuals with schizophrenia have some external validity.

Background The Oklahoma Trauma Registry (OTR) collects data from all state-licensed acute care hospitals. This study investigates trends and outcomes of trauma in Oklahoma using OTR. Methods 107,549 patients (2005–2014) with major severity and one of the following criteria were included: length of hospital stay ≥48 h, dead on arrival or death in the hospital, hospital transfer, ICU admission, or surgery on the head, chest, abdomen, or vascular system. Patient characteristics, mechanisms of injury, and outcomes of trauma were analyzed. Results Hospital admissions due to falls increased with an annual percent change of 4.0% (95%CI: 3.1%–4.9%) while hospital admissions due to motor vehicle crashes decreased. The number of overall deaths per year remained stable except for the fall-related deaths, which increased proportionate to the increase in the incidence of fall. Fall-related mortality was 4.2% and intracranial bleeding was present in 60% in these patients. Conclusion Falls are significantly increasing as a mechanism of trauma admissions and trauma-related deaths in Oklahoma. Analysis of state-based trauma registries can identify trends in etiologies of injuries and may indicate a reference point to prioritize preventive plans.

The authors compared the efficacy and tolerability of low and moderate dosages of extended-release quetiapine in adults with borderline personality disorder.Ninety-five participants with DSM-IV borderline personality disorder were randomly assigned to receive 150 mg/day of quetiapine (the low-dosage group; N=33), 300 mg/day of quetiapine (the moderate-dosage group; N=33), or placebo (N=29). Total score over time on the clinician-rated Zanarini Rating Scale for Borderline Personality Disorder ("Zanarini scale") was analyzed in a mixed-effects model accounting for informative dropout.Participants in the low-dosage quetiapine group had significant improvement on the Zanarini scale compared with those in the placebo group. Time to response (defined as a reduction of 50% or more on the Zanarini scale total score) was significantly shorter for both the low-dosage quetiapine group (hazard ratio=2.54, p=0.007) and the moderate-dosage quetiapine group (hazard ratio=2.37, p=0.011) than for the placebo group. Among participants who completed the study, 82% in the low-dosage quetiapine group were rated as "responders," compared with 74% in the moderate-dosage group and 48% in the placebo group. Treatment-emergent adverse events included sedation, change in appetite, and dry mouth. The overall completion rate for the 8-week double-blind treatment phase was 67% (67% for the low-dosage quetiapine group, 58% for the moderate-dosage quetiapine group, and 79% for the placebo group). Participants who experienced sedation were more likely to drop out.Participants treated with 150 mg/day of quetiapine had a significant reduction in the severity of borderline personality disorder symptoms compared with those who received placebo. Adverse events were more likely in participants taking 300 mg/day of quetiapine.

Background General cognitive ability is usually lower in individuals with schizophrenia, partly due to genetic influences. However, the specific genetic features related to general cognitive ability are poorly understood. Individual variation in a specific type of mutation, uncommon genetic deletions, has recently been linked with both general cognitive ability and risk for schizophrenia. Methods We derived measures of the aggregate number of "uncommon" deletions (i.e., those occurring in 3% or less of our combined samples) and the total number of base pairs affected by these deletions in individuals with schizophrenia ( n = 79) and healthy control subjects ( n = 110) and related each measure to the first principal component of a large battery of cognitive tests, a common technique for characterizing general cognitive ability. These two measures of mutation load were also evaluated for relationships with total brain gray matter, white matter, and lateral ventricle volume. Results The groups did not differ on genetic variables. Multivariate general linear models revealed a group (control subjects vs. patients)×uncommon deletion number interaction, such that the latter variable was associated with lower general cognitive ability and larger ventricles in patients but not control subjects. Conclusions These data suggest that aggregate uncommon deletion burden moderates central features of the schizophrenia phenotype.

Expertly collected, well-curated data sets consisting of comprehensive clinical characterization and raw structural, functional and diffusion-weighted DICOM images in schizophrenia patients and sex and age-matched controls are now accessible to the scientific community through an on-line data repository (coins.mrn.org). The Mental Illness and Neuroscience Discovery Institute, now the Mind Research Network (MRN, http://www.mrn.org/ ), comprised of investigators at the University of New Mexico, the University of Minnesota, Massachusetts General Hospital, and the University of Iowa, conducted a cross-sectional study to identify quantitative neuroimaging biomarkers of schizophrenia. Data acquisition across multiple sites permitted the integration and cross-validation of clinical, cognitive, morphometric, and functional neuroimaging results gathered from unique samples of schizophrenia patients and controls using a common protocol across sites. Particular effort was made to recruit patients early in the course of their illness, at the onset of their symptoms. There is a relatively even sampling of illness duration in chronic patients. This data repository will be useful to 1) scientists who can study schizophrenia by further analysis of this cohort and/or by pooling with other data; 2) computer scientists and software algorithm developers for testing and validating novel registration, segmentation, and other analysis software; and 3) educators in the fields of neuroimaging, medical image analysis and medical imaging informatics who need exemplar data sets for courses and workshops. Sharing provides the opportunity for independent replication of already published results from this data set and novel exploration. This manuscript describes the inclusion/exclusion criteria, imaging parameters and other information that will assist those wishing to use this data repository.

Two-photon laser scanning microscopy of calcium dynamics using fluorescent indicators is a widely used imaging method for large scale recording of neural activity in vivo. Here we introduce volumetric Two-photon Imaging of Neurons using Stereoscopy (vTwINS), a volumetric calcium imaging method that employs an elongated, V-shaped point spread function to image a 3D brain volume. Single neurons project to spatially displaced image pairs in the resulting 2D image, and the separation distance between images is proportional to depth in the volume. To demix the fluorescence time series of individual neurons, we introduce a novel orthogonal matching pursuit algorithm that also infers source locations within the 3D volume. We illustrate vTwINS by imaging neural population activity in mouse primary visual cortex and hippocampus. Our results demonstrate that vTwINS provides an effective method for volumetric two-photon calcium imaging that increases the number of neurons recorded while maintaining a high frame-rate.

The Caribbean islands form an archipelago connecting North and South America. They have all been colonised by European countries and share strong historical, social, economic and diplomatic links with North America. However, their blood transfusion services have evolved differently, using predominantly family/replacement rather than voluntary non-remunerated donors as has been the practice in England and America since 1926 and 1970, respectively. This article uses the case of Trinidad and Tobago to examine the history and current state of blood transfusion services in the Caribbean and to present early results of an initiative for improving blood safety and adequacy in the region.

This study aimed to examine the impact of quetiapine on the symptom and distress domains measured by the Symptom Checklist-90-Revised (SCL-90-R) in patients with borderline personality disorder (BPD).Ninety-five participants meeting DSM-IV diagnostic criteria for BPD were randomly assigned to low-dosage (quetiapine, 150 mg/d; n = 33), moderate-dosage (quetiapine, 300 mg/d; n = 33), or placebo (n = 29). SCL-90-R was administered weekly over the course of an 8-week double-blind treatment phase. We used a mixed-effects model to analyze subscale scores of the SCL-90-R.Results showed that both dosages of quetiapine were effective in reducing levels of overall psychological distress, interpersonal sensitivity, depression, and hostility compared with those who received placebo.SCL-90-R can be a useful tool that would allow clinicians to collect information in addition to the DSM symptoms to better understand the diagnostic heterogeneity found in patients diagnosed with BPD.

There is considerable evidence implicating brain white matter (WM) abnormalities in the pathophysiology of schizophrenia; however, the spatial localization of WM abnormalities reported in the existing studies is heterogeneous. Thus, the goal of this study was to quantify the spatial characteristics of WM abnormalities in schizophrenia. One hundred and fourteen patients with schizophrenia and 138 matched controls participated in this multisite study involving the Universities of Iowa, Minnesota, and New Mexico, and the Massachusetts General Hospital. We measured fractional anisotropy (FA) in brain WM regions extracted using 3 different image-processing algorithms: regions of interest, tract-based spatial statistics, and the pothole approach. We found that FA was significantly lower in patients using each of the 3 image-processing algorithms. The region-of-interest approach showed multiple regions with lower FA in patients with schizophrenia, with overlap at all 4 sites in the corpus callosum and posterior thalamic radiation. The tract-based spatial statistic approach showed (1) global differences in 3 of the 4 cohorts and (2) lower frontal FA at the Iowa site. Finally, the pothole approach showed a significantly greater number of WM potholes in patients compared to controls at each of the 4 sites. In conclusion, the spatial characteristics of WM abnormalities in schizophrenia reflect a combination of a global low-level decrease in FA, suggesting a diffuse process, coupled with widely dispersed focal reductions in FA that vary spatially among individuals (ie, potholes).

Structural brain measures are employed as endophenotypes in the search for schizophrenia susceptibility genes. We analyzed two independent structural imaging datasets with voxel-based morphometry and with source-based morphometry, a multivariate, independent components analysis, to determine the stability and heritability of regional gray matter concentration abnormalities in schizophrenia. The samples comprised 209 and 102 patients with schizophrenia and 208 and 96 healthy volunteers, respectively. The second sample additionally included non-ill siblings of participants with and without schizophrenia. A standard voxel-based analysis showed reproducible regional gray matter deficits in the affected participants compared with unrelated, unaffected controls in both datasets: patients showed significant gray matter concentration deficits in cortical frontal, temporal, and insular lobes. Source-based morphometry (SBM) was applied to the gray matter images of the entire sample to determine the effects of diagnosis on networks of covarying structures. The SBM analysis extracted 24 significant sets of covarying regions (components). Four of these components showed significantly lower gray matter concentrations in patients (p < .05). We determined the familiality of the observed SBM components based on 66 sibling pairs (25 discordant for schizophrenia). Two components, one including the medial frontal, insular, inferior frontal, and temporal lobes, and the other including the posterior occipital lobe, showed significant familiality (p < .05). We conclude that structural brain deficits in schizophrenia are replicable, and that SBM can extract unique familial and likely heritable components. SBM provides a useful data reduction technique that can provide measures that may serve as endophenotypes for schizophrenia.

OBJECTIVE To examine the efficacy and safety of olanzapine at low and moderate doses for the treatment of borderline personality disorder. METHOD In this 12-week randomized double-blind placebo-controlled trial, 451 outpatients aged 18-65 years with DSM-IV borderline personality disorder received olanzapine 2.5 mg/d (n = 150), olanzapine 5-10 mg/d (n = 148), or placebo (n = 153). The trial was conducted from February 2004 through January 2006 at 59 community-based and academic study centers in 9 countries (United States, Italy, Poland, Romania, Turkey, Chile, Peru, Argentina, and Venezuela). The primary efficacy measure was mean change from baseline to last-observation-carried-forward endpoint on the Zanarini Rating Scale for Borderline Personality Disorder (ZAN-BPD) total score. Secondary measures included the Montgomery-Asberg Depression Rating Scale, the Modified Overt Aggression Scale, the Global Assessment of Functioning, the Symptom Checklist-90-Revised, and the Sheehan Disability Scale. RESULTS An overall mean baseline ZAN-BPD total score of 17.2 (SD = 4.9) indicated moderate symptom severity. Only treatment with olanzapine 5-10 mg/d was associated with significantly greater mean change from baseline to endpoint in ZAN-BPD total score relative to placebo (-8.5 vs -6.8, respectively; P = .010; effect size = 0.29; 95% CI, 0.06-0.52). Response rates (response indicated by ≥ 50% decrease from baseline in ZAN-BPD total score) were significantly higher for olanzapine 5-10 mg/d (73.6%) versus olanzapine 2.5 mg/d (60.1%; P = .018) and versus placebo (57.8%; P = .006). Time to response was also significantly shorter for patients taking olanzapine 5-10 mg/d than for placebo-treated patients (P = .028). Treatment-emergent adverse events reported significantly more frequently among olanzapine-treated patients included somnolence, fatigue, increased appetite, and weight increase (all P values < .05). Mean weight change from baseline to endpoint was significantly greater for olanzapine-treated than for placebo-treated patients (olanzapine 2.5 mg/d: 2.09 kg; olanzapine 5-10 mg/d: 3.17 kg; placebo: 0.02 kg; P < .001). The overall completion rate for the 12-week double-blind treatment period was 65.2% (ie, 64.7% for olanzapine 2.5 mg/d, 69.6% for olanzapine 5-10 mg/d, and 61.4% for placebo). CONCLUSIONS Olanzapine 5-10 mg/d showed a clinically modest advantage over placebo in the treatment of overall borderline psychopathology. This advantage in effectiveness should be weighed against the risk of adverse events (particularly weight gain), which were consistent with the known safety profile of olanzapine. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00088036.

Background: Emerging evidence implicates white matter (WM) abnormalities in the pathophysiology of schizophrenia. However, there is considerable heterogeneity in the presentation of WM abnormalities in the existing studies. The object of this study was to evaluate WM integrity in a large sample of patients with first-episode (FE) and chronic schizophrenia in comparison to matched control groups. Our goal was to assess whether WM findings occurred early in the illness or whether these abnormalities developed with the illness over time. Methods: Participants included 114 patients with schizophrenia (31 FE and 83 chronic patients) and 138 matched controls. High-resolution structural and diffusion tensor images were obtained on all participants. Measures of fractional anisotropy (FA) were calculated for the 4 cortical lobes and the cerebellum and brain stem. Results: FA was significant lower in patients vs controls in the whole brain and individually in the frontal, parietal, occipital, and temporal lobes. FA was not significantly different in the brain stem or cerebellum. FA differences were significant only in patients with chronic schizophrenia and not in the FE group. Conclusions: We found global differences in the WM microstructure in patients with chronic but not FE schizophrenia. These findings suggest progressive alterations in WM microstructure.

Objective This study investigates the utility of the cutaneous silent period (CuSP) in evaluating patients with carpal tunnel syndrome (CTS). Methods The authors measured the CuSP from the abductor pollicis brevis muscle in 135 hands of patients with idiopathic CTS and 30 hands of age- and gender-matched controls. The patient group was further divided into subgroups according to the Canterbury scale. The differences in parameters between the patient subgroups and control group were analysed. A predetermined analysis looked at the possible correlation between the CuSP and symptom severity as measured by the Boston-Questionnaire. Results The mean CuSP latencies in the patient group (72.4±16.1ms) was significantly longer than the control group (64.6±13.4ms; P =0.014), although there was no difference in the duration of the CuSP between groups. The duration and latency of the CuSP correlated to a higher severity on the Canterbury scale ( r =0.273, P r =−0.164, P =0.036, respectively). However, the CuSP parameters did not correlate with the Boston-Questionnaire scores. Conclusions Although patients with CTS had significantly prolonged CuSP latency, the CuSP did not correlate with the clinical symptoms scale. Significance The CuSP is a useful ancillary test to evaluate Aδ fibre function; however, it is not a reliable tool to quantify clinical severity.

A number of recent studies have combined multiple experimental paradigms and modalities to find relevant biological markers for schizophrenia. In this study, we extracted fMRI features maps from the analysis of three experimental paradigms (auditory oddball, Sternberg item recognition, sensorimotor) for a large number (n=154) of patients with schizophrenia and matched healthy controls. We used the general linear model (GLM) and independent component analysis (ICA) to extract feature maps (i.e. ICA component maps and GLM contrast maps), which were then subjected to a coefficient-constrained independent component analysis (CCICA) to identify potential neurobiological markers. A total of 29 different feature maps were extracted for each subject. Our results show a number of optimal feature combinations that reflect a set of brain regions that significantly discriminate between patients and controls in the spatial heterogeneity and amplitude of their feature signals. Spatial heterogeneity was seen in regions such as the superior/middle temporal and frontal gyri, bilateral parietal lobules, and regions of the thalamus. Most strikingly, an ICA feature representing a bilateral frontal pole network was consistently seen the ten highest feature results when ranked on differences found in the amplitude of their feature signals. The implication of this frontal pole network and the spatial variability which spans regions comprising of bilateral frontal/temporal lobes and parietal lobules suggests that these regions might play a significant role in the pathophysiology of schizophrenia.

This prospective study was performed to evaluate the effect of chemotherapy-related neurotoxicity on quality of life (QOL) of patients with lymphoma.Thirty-two patients with diffuse large B-cell or follicular lymphoma without prior evidence of neuropathy were enrolled. Patients underwent the evaluations based on neuropathy symptom and disability score, nerve conduction studies, and SF-36 questionnaire for QOL assessment. They received six cycles of chemotherapy every three weeks, and all evaluations were repeated during and after the completion of 6th cycle.Sensory neuropathy-associated symptoms were observed in 27 patients (84.4%), and polyneuropathy was confirmed by nerve conduction study in 14 patients (43.8%). These patients with polyneuropathy showed worse QOL in domains mainly associated with physical health status including "physical function" compared to patients without polyneuropathy. There was a significant association of neuropathy symptom and disability scores with "bodily pain" and "vitality" of QOL domains. The serial evaluations of patients with neuropathy showed a worsening of QOL and neuropathy symptom scores during chemotherapy, then improvement of these values after chemotherapy. Thus, the final nerve conduction study confirmed the decrease in polyneuropathy compared to the 2nd evaluation (P = 0.032).Chemotherapy-related polyneuropathy may deteriorate QOL of patients with lymphoma, mainly physical health-associated QOL.

When both structural magnetic resonance imaging (sMRI) and functional MRI (fMRI) data are collected they are typically analyzed separately and the joint information is not examined. Techniques that examine joint information can help to find hidden traits in complex disorders such as schizophrenia. The brain is vastly interconnected, and local brain morphology may influence functional activity at distant regions. In this paper we introduce three methods to identify inter-correlations among sMRI and fMRI voxels within the whole brain. We apply these methods to examine sMRI gray matter data and fMRI data derived from an auditory sensorimotor task from a large study of schizophrenia. In Method 1 the sMRI-fMRI cross-correlation matrix is reduced to a histogram and results show that healthy controls (HC) have stronger correlations than do patients with schizophrenia (SZ). In Method 2 the spatial information of sMRI-fMRI correlations is retained. Structural regions in the cerebellum and frontal regions show more positive and more negative correlations, respectively, with functional regions in HC than in SZ. In Method 3 significant sMRI-fMRI inter-regional links are detected, with regions in the cerebellum showing more significant positive correlations with functional regions in HC relative to SZ. Results from all three methods indicate that the linkage between gray matter and functional activation is stronger in HC than SZ. The methods introduced can be easily extended to comprehensively correlate large data sets.

The impact of informal care responsibilities on the willingness and ability of caregivers to undertake paid employment has been the subject of a number of studies. In contrast, the effect of employment status on willingness to undertake informal care has been less well explored. This paper concentrates on this less-studied direction of causality using the data provided by 15 waves of the British Household Panel Survey. We find that employment participation and earnings both impact negatively on willingness to supply informal care. This evidence has implications for health and social care policy since informal care has been shown to be a significant substitute for formal long-term care.

Sixteen Stanford University Medical Center (SUMC) patients with foraminal nerve sheath tumors had charts reviewed. CyberKnife radiosurgery was innovative in management. Parameters were evaluated for 16 foraminal nerve sheath tumors undergoing surgery, some with CyberKnife. Three neurofibromas had associated neurofibromatosis type 1 (NF1). Eleven patients had one resection; others had CyberKnife after one (two) and two (three) operations. The malignant peripheral nerve sheath tumor (MPNST) had prior field-radiation and adds another case. Approaches included laminotomy and laminectomies with partial (three) or total (two) facetectomies/fusions. Two cases each had supraclavicular, lateral extracavitary, retroperitoneal and Wiltze and costotransversectomy/thoracotomy procedures. Two underwent a laminectomy/partial facetectomy, then CyberKnife. Pre-CyberKnife, one of two others had a laminectomy/partial facetectomy, then total facetectomy/fusion and the other, two supraclavicular approaches. The MPNST had a hemi-laminotomy then laminectomy/total facetectomy/fusion, followed by CyberKnife. Roots were preserved, except in two. Of 11 single-operation-peripheral nerve sheath tumors, the asymptomatic case remained stable, nine (92%) improved and one (9%) worsened. Examinations remained intact in three (27%) and improved in seven (64%). Two having a single operation then CyberKnife had improvement after both. Of two undergoing two operations, one had symptom resolution post-operatively, worsened 4 years post-CyberKnife then has remained unchanged after re-operation. The other such patient improved post-operatively, had no change after re-operation and improved post-CyberKnife. The MPNST had presentation improvement after the first operation, worsened and after the second surgery \and CyberKnife, the patient expired from tumor spread. In conclusion, surgery is beneficial for pain relief and function preservation in foraminal nerve sheath tumors. Open surgery with CyberKnife is an innovation in these tumors’ management.

Summary There is little information on the molecular basis of intrafamilial and inter-familial phenotypic heterogeneity with the same androgen receptor (AR) mutation in patients with partial androgen insensitivity syndrome. A genetic analysis was performed in a large kindred with ambiguous genitalia and the genotype–phenotype correlations were analysed. The index case was brought for sex assignment. Family history revealed four other affected members who had hypospadias and varying degrees of virilisation. All the affected males had hemizygous mutations in the third exon of the AR gene (A596T). One was also found to have a heterozygous mutation in the fourth exon of the 5 alpha reductase type 2 gene (G196S). This affected male with double mutations was better virilised compared with the other affected members with a single mutation. The degree of virilisation correlated with serum testosterone levels. Gynaecomastia was not present in any of these subjects. It is concluded that the subject with dual gene defects also had higher levels of testosterone and pubertal virilsation. Testosterone levels possibly govern the degree of pubertal virilisation in subjects with A596T gene defects. It is not clear whether the better pubertal virilsation and higher testosterone are in any way causally related to the SRD5A2 gene defect.

Transplantation of muscle precursor cells (MPCs) is a promising approach for the treatment of muscular dystrophies. However, preclinical and clinical results have shown that the technology is not yet efficient enough for most therapeutic applications. Among the problems that remain unsolved are low cellular survival, poor proliferation and lack of migration of the transplanted cells. One major technical hurdle for the optimization of transplantation protocols is how to follow precisely the fate of the cells after transplantation. In this study, we examined the use of a secreted form of the mouse alkaline phosphatase (mSeAP) enzyme as the reporter system transduced into MPCs using a retroviral vector. We show that circulating mSeAP could be detected in the serum of the transplanted mice at different time points after MPC transplantation. We also found that the level of circulating mSeAP is highly correlated with the number of transplanted cells and that mSeAP is an excellent histological marker. Further, studying the levels of circulating mSeAP compared with the number of muscle fibers positive to mSeAP and to dystrophin, enabled detailed analyses of bottleneck steps for successful transplantation. Taken together, our results show that mSeAP is an excellent quantitative 'real-time' reporter gene for cell therapy preclinical studies.

Regional gray matter (GM) abnormalities are well known to exist in patients with chronic schizophrenia. Voxel-based morphometry (VBM) has been previously used on structural magnetic resonance images (MRI) data to characterize these abnormalities. Two multisite schizophrenia studies, the Functional Biomedical Informatics Research Network and the Mind Clinical Imaging Consortium, which include 9 data collection sites, are evaluating the efficacy of pooling structural imaging data across imaging centers. Such a pooling of data could yield the increased statistical power needed to elucidate effects that may not be seen with smaller samples. VBM analyses were performed to evaluate the consistency of patient versus control gray matter concentration (GMC) differences across the study sites, as well as the effects of combining multisite data. Integration of data from both studies yielded a large sample of 503 subjects, including 266 controls and 237 patients diagnosed with schizophrenia, schizoaffective or schizophreniform disorder. The data were analyzed using the combined sample, as well as analyzing each of the 2 multisite studies separately. A consistent pattern of reduced relative GMC in schizophrenia patients compared with controls was found across all study sites. Imaging center-specific effects were evaluated using a region of interest analysis. Overall, the findings support the use of VBM in combined multisite studies. This analysis of schizophrenics and controls from around the United States provides continued supporting evidence for GM deficits in the temporal lobes, anterior cingulate, and frontal regions in patients with schizophrenia spectrum disorders.

BackgroundDespite the prevalence and clinical significance of borderline personality disorder, its treatment remains understudied.AimsTo evaluate treatment with variably dosed olanzapine in individuals with borderline personality disorder.MethodIn this 12-week randomised, double-blind trial, individuals received olanzapine (2.5–20 mg/day;n=155) or placebo (n=159) (trial registry: NCT00091650). The primary efficacy measure was baseline to end-point change on the Zanarini Rating Scale for Borderline Personality Disorder (ZAN–BPD) using last-observation-carried-forward methodology.ResultsBoth olanzapine and placebo groups showed significant improvements but did not differ in magnitude at end-point (76.56v. 76.25,P=0.661). Response rates (50% reduction in ZAN–BPD) were 64.7% with olanzapine and 53.5% with placebo (P=0.062); however, time to response was significantly shorter for olanzapine (P=0.022). Weight gain was significantly greater (2.86v. 70.35 kg, P50.001), with higher incidence of treatment-emergent abnormal high levels of prolactin for the olanzapine group.ConclusionsIndividuals treated with olanzapine and placebo showed significant but not statistically different improvements on overall symptoms of borderline personality disorder. The types of adverse events observed with olanzapine treatment appeared similar to those observed previously in adult populations.

Objective There is emerging evidence that aberrations in the integrity of cerebral white matter tracts, especially those connected to limbic structures, play a role in the pathophysiology of schizophrenia. The fornix is the primary efferent neural pathway of the hippocampus and has been shown to be abnormal in adults with schizophrenia. Method High-resolution structural magnetic resonance imaging and diffusion tensor images were obtained on 15 patients with childhood- and adolescent-onset schizophrenia and 15 age- and sex-matched controls. Measures of cross-sectional area and water diffusion properties were obtained on regions of interest of the fornix performed by a trained radiologist. Results The volume of the fornix was significantly smaller (10.9%) in children and adolescents with schizophrenia compared to controls (Cohen d = 0.87, p = .025). There were no significant differences between the fractional anisotropy or mean diffusivity between the groups. Conclusions These findings suggest that the early stages of schizophrenia are associated with a decrease in fornix volume without microstructural white matter changes. The volume differences may reflect an early insult to neighboring brain regions (i.e., hippocampus), that could decrease the number of efferent fibers without necessarily disrupting fiber integrity. J. Am. Acad. Child Adolesc. Psychiatry , 2008; 47(7):826–832.

Objective: To evaluate the efficacy and tolerability of extended release quetiapine fumarate (quetiapine XR) in a 6-week, double-blind, randomized study. Method: Patients with a DSM-IV diagnosis of acute schizophrenia were randomly assigned to fixed-dose quetiapine XR 400, 600, or 800 mg/day (once daily in the evening), quetiapine immediate release (IR) 400 mg/day (200 mg twice daily), or placebo. Dual-matched placebo was used to maintain blinding. Quetiapine XR target doses were reached by day 2 (400 and 600 mg) and day 3 (800 mg). The primary endpoint was least squares mean change from baseline to week 6 in Positive and Negative Syndrome Scale (PANSS) total score. PANSS response rate (percentage of patients with >= 30% reduction in total score), Clinical Global Impressions-Improvement scale (CGI-I) response rate (percentage of patients with score :! 3), change in CGI-Severity of Illness (CGI-S), and adverse events (AEs) were also assessed. The study was conducted from November 2004 to December 2005. Results: 588 patients were enrolled and 446 (76%) completed the study. Improvement in PANSS total score at week 6 was significant versus placebo (-18.8) in all groups: -24.8 (p = .03), -30.9 (p

The aims of this study were to determine the factors that influence blood donation in different demographic groups in a multi-ethnic, multicultural community, and to devise a strategy for a national campaign to increase voluntary non-remunerated blood donations. The majority (87%) of blood donations in Trinidad and Tobago are replacement donations. Seventy per cent of the country's transfusion needs are not met. In 1998, the World Health Assembly recommended that reliance on replacement donations should be phased out due to their association with an increased risk of transfusion-transmitted infections. An observer-administered questionnaire was completed by 1423 respondents in a multi-ethnic borough in central Trinidad. Respondents were classified as donors or non-donors and grouped by age, race, religion, employment status and highest level of education. The prevalence of a history of blood donation and the factors that encouraged donation or conversely discouraged donation in each demographic group were recorded. A total of 1146 (81.2%) respondents had never donated blood. Of the 277 (18.8%) who had previously donated, replacement for a family member or friend was the most common reason (86.9%). The prevalence of donation was low in all racial, religious, gender, educational and age groups. However, there were significant demographic variations. The majority (71.3%) of non-donors cited a lack of information as a major reason for non-donation and expressed a willingness to donate if access to information and donation facilities were improved. Voluntary blood donation in Trinidad and Tobago could be greatly increased by a national education campaign and increased accessibility to donation centres. This would ensure a safer and more reliable blood supply.

This editorial refers to ‘Ranking of psychosocial and traditional risk factors by importance for coronary heart disease: the Copenhagen City Heart Study’, by P. Schnohr et al. on page doi:10.1093/eurheartj/ehv027 Popular and widespread beliefs associate emotions and environmental factors with cardiovascular diseases. Over 2000 years ago, the Roman physician Celsus noted, ‘fear and anger, and any other state of mind may often be apt to excite the pulse’. William Harvey in 1628 wrote, ‘every affection of the mind that is attended by either pain or pleasure, hope or fear, is the cause of agitation whose influence extends to the heart’. These and many other observations became established as scientists in the 20th century began to explore associations of psychosocial factors with the genesis of acute and chronic cardiovascular diseases. As shown in Figure 1 , numerous individual and environmental factors are proposed, and many are found to predict increased disease outcomes. These factors range from natural disasters such as earthquakes to social conditions to personality disorders to emotions. However, while there are many strong associations between psychosocial measures and cardiovascular diseases, after adjustment for known classical risk factors, psychosocial measures have never reached a status requiring physician measurement and treatment. Figure 1 Psychosocial factors associated with cardiovascular disease. The potential reasons for this disconnect between observational studies with significantly increased relative risks and therapeutic interventions are several, including the following. …

This study aims to extend previous research by considering gender differences in borderline personality (BPD) using both dimensional selfreported and clinical measures of symptomatology. Drawing from a cross- cultural, clinical trial sample, the authors compared female and male BPD subjects (N = 770; 211 male) between the ages of 18 and 65 using diagnostic and self- report data. The authors found that women with BPD have greater hostility and relationship disruption than men. Gender differences in eating disorders, particularly bulimia, are more divergent than in the general population. Generally, gender differences in BPD in this sample are consistent with known general population differences. Women show greater overall symptomatology, including depressive, anxious, and somatic symptoms. Men have higher rates of antisocial personality disorder and a trend toward higher rates of narcissistic personality disorder. However, several gender differences consistently found in the general population are not present in this BPD sample. There are no differences in aggression, suicidality, substance abuse, panic disorder, or obsessive- compulsive disorder. Gender differences in major depression and posttraumatic stress disorder are attenuated. These findings support the conclusion that BPD may diminish normal gender differences. Borderline personality disorder (BPD) is a complex and serious psychiatric disorder associated with severe functional impairment. There has been some controversy regarding gender disparity in the prevalence of BPD. A meta- analysis of clinical studies showed that females make up 76% of individuals with BPD (Widiger & Trull, 1993). These results are probably due to sampling bias rather than a reflection of a true female preponder ance (Skodol & Bender, 2003). Epidemiological studies have not found a

We observed consecutive hospital admissions for acute painful crisis (APC) among adults with Sickle Cell Disease (SCD) over a 6-month period in Trinidad and Tobago. Episodes (111) of APC resulted in 82 admissions of 59 patients. The most common site for pain was the trunk. Patients ranged in age from 17 to 53 years (median: 25). Median length of hospital stay was 4 days. Total dose of Pethidine given per admission ranged from 100 to 1650 mg (median: 525). The mean dose of morphine was 70 mg. Six (7%) of patients were readmitted within 10 days of discharge. Twenty-five (30%) of patients had chest pain at presentation of whom 10 (12%) had consolidation on chest X-ray, defining the acute chest syndrome (ACS). There was one death caused by biliary sepsis. The study revealed seemingly low opiate usage for in-hospital treatment of APC with acceptable rates of readmission. The BCSH 2003 guidelines seemed applicable apart for the choice and route of fluid for rehydration and opiate analgesia.

The differential diagnosis between schizophrenia and bipolar disorder during adolescence presents a major clinical problem. Can these two diagnoses be differentiated objectively early in the courses of illness?We used linear discrimination analysis (LDA) to classify 28 adolescent subjects into one of three diagnostic categories (healthy, N=8; schizophrenia, N=10; bipolar, N=10) using subsets from a pool of 45 variables as potential predictors (22 neuropsychological test scores and 23 quantitative structural brain measurements). The predictor variables were adjusted for age, gender, race, and psychotropic medication. All possible subsets composed of k=2-12 variables, from the set of 45 variables available, were evaluated using the robust leaving-one-subject-out method.The highest correct classification (96%) of the 3 diagnostic categories was yielded by 9 sets of k=12 predictors, comprising both neuropsychological and brain structural measures. Although each one of these sets misclassified one case, each set correctly classified (100%) at least one group, such that a fully correct diagnosis could be reached by a tree-type decision procedure.We conclude that LDA with 12 predictor variables can provide correct and robust classification of subjects into the three diagnostic categories above. This robust classification relies upon both neuropsychological and brain structural information. Our results demonstrate that, despite overlapping clinical symptoms, schizophrenia and bipolar disorder can be differentiated early in the course of disease. This finding has two important implications. Firstly, schizophrenia and bipolar disorder are different illnesses. If schizophrenia and bipolar are dissimilar clinical manifestations of the same disease, we would not be able to use non-clinical information to classify ('diagnose') schizophrenia and bipolar disorder. Secondly, if this study's findings are replicated, brain structure (MRI) and brain function (neuropsychological) used together may be useful in the diagnosis of new patients.

Quantitation of glutathione (GSH) in the human brain in vivo using short echo time 1H NMR spectroscopy is challenging because GSH resonances are not easily resolved. The main objective of this study was to validate such quantitation in a clinically relevant population using the resolved GSH resonances provided by edited spectroscopy. A secondary objective was to compare several of the neurochemical concentrations quantified along with GSH using LCModel analysis of short echo time spectra in schizophrenia versus control.GSH was quantified at 4T from short echo STEAM spectra and MEGA-PRESS edited spectra from identical volumes of interest (anterior cingulate) in ten volunteers. Neurochemical profiles were quantified in nine controls and 13 medicated schizophrenic patients.GSH concentrations as quantified using STEAM, 1.6 +/- 0.4 micromol/g (mean +/- SD, n = 10), were within error of those quantified using edited spectra, 1.4 +/- 0.4 micromol/g, and were not different (p = 0.4). None of the neurochemical measurements reached sufficient statistical power to detect differences smaller than 10% in schizophrenia versus control. As such, no differences were observed.Human brain GSH concentrations can be quantified in a clinical setting using short-echo time STEAM spectra at 4T.

Sixteen controlled laboratory studies, involving 420 kittens and cats, were conducted to evaluate the efficacy and safety of topically applied formulations of imidacloprid and moxidectin for the prevention of feline heartworm disease, treatment of flea infestations and treatment and control of intestinal nematodes. Unit-dose applicators and the dosing schedule used in these studies were designed to provide a minimum of 10 mg imidacloprid and 1 mg moxidectin/kg. Treatments were applied topically by parting the hair at the base of the skull and applying the solution on the skin. Imidacloprid treatment alone did not display activity against Dirofilaria immitis or intestinal nematodes and moxidectin treatment alone provided little or no activity against adult Ctenocephalides felis infestations. The formulation containing 10% imidacloprid and 1% moxidectin was 100% efficacious against the development of adult D. immitis infections when cats were treated 30 days after inoculation with third-stage larvae. A single treatment with this formulation also provided 88.4–100% control of adult C. felis for 35 days. Imidacloprid/moxidectin was 100% efficacious against adult Toxocara cati and 91.0–98.3% efficacious against immature adults and fourth-stage T. cati larvae. The formulation provided 98.8–100% efficacy against adult Ancylostoma and immature adults and third-stage A. tubaeforme larvae. Monthly topical application with 10% imidacloprid/1% moxidectin is convenient, efficacious and safe for the prevention of feline heartworm disease, treatment of flea infestation and for the treatment and control of intestinal nematode infections of cats.

We compared 79 simultaneous marrow aspirates and trephine biopsies from multiple myeloma patients for sensitivity, concordance, quality and clinical relevance. A total of 60 examinations had been performed for initial diagnosis, i.e. in cases of suspected myeloma and 19 at follow-up. Of which, 45 (57%) of trephine biopsies were less than 1.6 cm before processing and 33 (42%) were crushed and/or fragmented. Overall, only 19/79 (24%) of trephine biopsy specimens were of at least 1.6 cm length prior to processing and not disrupted. On the other hand, 75% of aspirates were particulate and satisfactory. Mean time between receipt of a trephine biopsy specimen and issuance of a histopathological report was 9 days. Although 40% of trephine biopsies yielded information that could not be reliably obtained from a bone marrow aspirate such information was in all cases clinically irrelevant or obtainable by non-invasive means. In all cases where myeloma was detected in a trephine biopsy it was also detected in a simultaneous bone marrow aspirate, if particulate. However, there were four (5%) cases in which myeloma was detected in such aspirates but not in simultaneously taken trephine biopsies. In cases (n=19) where repeat aspirates/trephine biopsies were taken for surveillance, concordance was found between reported changes in plasma cell ratio. Our data failed to demonstrate any added benefit from routinely performing trephine biopsies after a particulate specimen had been aspirated for the diagnosis or surveillance of myeloma. Furthermore, they suggest that particulate aspirates may be at least as sensitive as trephine biopsies for detecting myeloma.

This study assessed the ability of recombinant human stem cell factor (rHuSCF) to mobilize stem cells in 44 patients who had failed a prior mobilization (CD34(+) yield 0.5-1.9 x 10(6)/kg BW) with filgrastim-alone or chemotherapy-plus-filgrastim. The same mobilization regimen was used with the addition of rHuSCF. In the filgrastim-alone group (n=13), rHuSCF 20 microg/kg was started 3 days before filgrastim and continued for the duration of filgrastim. In the chemotherapy-plus-filgrastim group (n=31), rHuSCF 20 microg/kg/day plus filgrastim 5-10 microg/kg/day were administered concurrently. Leukaphereses were continued to a maximum of four procedures or a target of >or=3 x 10(6) CD34(+) cells/kg. In both groups, CD34(+) yield (x 10(6)/kg BW) of the study mobilization was higher than that of the prior mobilization (median: 2.42 vs 0.84 P=0.002 and 1.64 vs 0.99 P=

Several reports have noted an increase in white matter hyperintensities (WMH) on MRI scans of adult patients with bipolar disorder. We investigated whether this increase was also evident in a group of adolescent patients with bipolar disorder. The sample consisted of 15 bipolar patients, 19 patients with schizophrenia and 16 healthy comparison subjects. All subjects were adolescents. WMH were blindly rated on T2-weighted and PD-weighted MRI scans using our own scale with documented inter-rater reliability. WMH were present in 10 of 15 bipolar patients (67%), seven of 19 patients with schizophrenia (37%) and five of 16 comparison subjects (31%). The bipolar adolescent group had a statistically significant increased presence of WMH compared both with healthy comparison subjects and the schizophrenic group. The association between WMH and bipolar disorder appears to extend to the adolescent years.

The University Hospitals Paris Centre Pharmacy compounds three concentrations of cyclosporine eye drops: 20mg/mL (=2%); 5mg/mL (=0.5%) and 0.5mg/mL (=0.05%). Cyclosporine A 2% drops were developed in 1995 to prevent the rejection of high-risk cornea transplants after failure of topical steroids. The other concentrations of eye drops were developed for the treatment of various immune or inflammatory diseases of the cornea, conjunctiva and uvea. These eye drops are dispensed with a physician's prescription to hospitalized or ambulatory patients. A retrospective study over 4 years (2009-2013) was conducted to analyze the details of prescription and possible adverse events.Dispensations made from January 1st, 2009 through December 31st, 2013 were studied, including patient age, dose of cyclosporine and practice location of prescribing physician. We also recorded the indications for cyclosporine eye drops in a sample of ambulatory patients. The analysis of local tolerability and the effect on visual comfort was based on questionnaires sent to the patients on cyclosporine 2% over a period of 2 months.Cyclosporine eye drops prescription grew continuously from 2009 through 2013 for all concentrations. In 2013, 5,859 patients were treated, among which 3,616 patients with topical cyclosporine 2%, 1,681 patients with 0.5%, and 562 patients with 0.05%. In total, this represents 62,621 eye drops. Treated patients ranged from 1 week to 100 years old. Topical 2% cyclosporine is indicated in 61% of cases to prevent high-risk corneal graft rejection. Other indications are corneal ulcer (6%), atopic keratoconjunctivitis (5%), vernal keratoconjunctivitis (5%) and herpetic keratitis (4%). Topical 0.5% cyclosporine is prescribed primarily for dry eye syndrome (20%) and to prevent rejection of high-risk corneal transplantation (11%), to treat ocular rosacea (10%), vernal keratoconjunctivitis (10%), atopic keratoconjunctivitis (8%) and Sjögren's syndrome (7%). Topical 0.05% cyclosporine is prescribed primarily for dry eye syndrome resistant to conventional treatment (47%) and Sjögren's syndrome (21%). Local tolerability of topical cyclosporine was evaluated in 388 patients. The majority of patients (63%) did not experience any adverse effects. The main side effects are redness, burning sensation and itching.Prescription of various formulations of topical cyclosporine is current practice for surgical indications: rejection of high-risk corneal transplantation; or medical indications: vernal or atopic keratoconjunctivitis and dry eye syndrome. Further prospective randomized studies would be necessary to validate formulations, doses and indications of cyclosporine eye drops.

Borderline personality disorder (BPD) is a serious mental illness that can cause significant suffering and carries a risk of suicide. Assigning an accurate diagnosis is critical to guide treatment. Currently, the diagnosis of BPD is made exclusively through the use of clinical assessment; no objective test is available to assist with its diagnosis. Thus, it is highly desirable to explore quantitative biomarkers to better characterize this illness. In this study, we extract spectral power features from the power spectral density and cross spectral density of resting-state fMRI data, covering 20 brain regions and 5 frequency bands. Machine learning approaches are employed to select the most discriminating features to identify BPD. Following a leave-one-out cross validation procedure, the proposed approach achieves 93.55% accuracy (100% specificity and 90.48% sensitivity) in classifying 21 BPD patients from 10 healthy controls based on the top ranked features. The most discriminating features are selected from the 0.1~0.15 Hz frequency band, and are located at the left medial orbitofrontal cortex, the left thalamus, and the right rostral anterior cingulate cortex. The high classification accuracy indicates the discriminating power of the spectral power features in BPD identification. The proposed machine learning approach may be used as an objective test to assist clinical diagnosis of BPD.

Background Cognitive deficits are prominent in schizophrenia and represent promising endophenotypes for genetic research. Methods The current study investigated the importance of two conceptually distinct genetic aggregates, one based on copy number variations (uncommon deletion burden), and one based on single nucleotide polymorphisms identified in recent risk studies (genetic risk score). The impact of these genetic factors, and their interaction, was examined on cognitive endophenotypes defined by principal component analysis (PCA) in a multi-center sample of 50 patients with schizophrenia and 86 controls. PCA was used to identify three different types of executive function (EF: planning, fluency, and inhibition), and in separate analyses, a measure general cognitive ability (GCA). Results Cognitive deficits were prominent among individuals with schizophrenia, but no group differences were evident for either genetic factor. Among patients the deletion burden measures predicted cognitive deficits across the three EF components and GCA. Further, an interaction was noted between the two genetic factors for both EF and GCA and the observed patterns of interaction suggested antagonistic epistasis. In general, the set of genetic interactions examined predicted a substantial portion of variance in these cognitive endophenotypes. Limitations Though adequately powered, our sample size is small for a genetic study. Conclusions These results draw attention to genetic interactions and the possibility that genetic influences on cognition differ in patients and controls.

The purpose of this study is to characterize the clinico-epidemiologic variables of patients with hip fracture and assess the presence of complications, whether dependent or independent of performing surgery within 48 hours of the fracture.A descriptive applied cross-sectional study of patients who underwent hip surgery was performed. Five hundred patients were included; females were predominant as they accounted for 68% (339); mean age was 75.5 years. Hypertension and diabetes mellitus were the most frequent conditions. Pertrochanteric fractures represented 56% (257) and were predominant.Mean operative time was 1.2 hours; and partial hip prosthesis accounted for 25.6% (128) and was the most common surgery performed, followed by plate osteosynthesis, which accounted for 25.4% (127) of the 457 procedures performed. The complication rate was 17%, with bronchopneumonia (2%) as the most frequent one; reoperation was the most frequent surgical complication (7.4%). Mean waiting time before surgery ranged from 72 hours to 14 days (73.2%) and mean hospital stay ranged between 7 and 15 days (37%).The highest incidence of fractures occurs in females over age 75. The most frequent fracture is the pertrochanteric one, with a high incidence of chronic-degenerative conditions that results in increased postoperative complications when surgical treatment is provided after 48 hours.

Posttraumatic stress disorder (PTSD) patients with histories of cocaine and alcohol abuse (CA-PTSD) were compared with normal volunteers. Positron emission tomography (PET) scans with 15O-butanol were used to compare regional cerebral blood flow (rCBF) between the groups during rest and during an auditory continuous performance task (ACPT). CA-PTSD patients had significantly higher rCBF in right amygdala and left parahippocampal gyrus than normals during the ACPT. Normals had higher rCBF at frontal cortex during the resting scan and during the ACPT. The role of the amygdala in attention and fear conditioning suggests that increased amygdala rCBF may be related to clinical features of PTSD. Cocaine use may be associated with increased amygdala rCBF in PTSD patients. Amygdala and frontal cortex attention system components may be reciprocally related and their relative contributions to processing of neutral stimuli perturbed in CA-PTSD.

Background: Numerous medications have been tested in patients with borderline personality disorder (BPD) and/or schizotypal personality disorder (SPD). Although many of the medications tested have been demonstrated to be useful, no clear main treatment for BPD has emerged. Despite the efficacy of some of the medicines, acceptability and side effects have proven to be barriers to the use of medication. Therefore, an open-label olanzapine trial utilizing objective ratings was performed. Methods: Patients suffering from BPD and dysthymia were included in an 8-week, open-label study of olanzapine monotherapy. The first 4 weeks of the trial allowed for flexible dosing; during the last 4 weeks, olanzapine dose was held constant. Patients were rated on Hopkins Symptoms Checklist 90 (SCL-90), Brief Psychiatric Rating Scale (BPRS), Global Assessment of Function (GAF), Barratt Impulsivity Scale (BIS 11), and Buss-Durkee Hostility Inventory (BDHI). Results: Eleven patients completed at least 2 weeks; nine of the patients finished the entire trial. There was a robust and statistically significant reduction in the five global ratings. Within the global ratings, symptoms of psychoticism, depression, interpersonal sensitivity, and anger were among the symptoms to be reduced. No movement disorder symptoms were noted for any of the patients. Conclusions: In this open-label pilot study, patients treated with olanzapine showed statistically significant reduction in self-rated and clinician-rated scales. Symptoms associated with BPD and dysthymia were among those to be substantially reduced. Further studies to explore olanzapine’s efficacy versus placebo, as well as comparison to other potential treatments for BPD, are important next steps.

The purpose of this study was to compare thalamic size in adolescent patients with either schizophrenia or bipolar disorder and healthy controls. T2-weighted axial magnetic resonance images were used to manually define the area of the thalamus for 20 schizophrenia patients, 15 bipolar patients and 16 normal control subjects, all of whom were adolescents. Two orthogonal planned contrasts were tested: Contrast 1, patients with schizophrenia vs. patients with bipolar disorder; and Contrast 2, both patient groups taken as a single group compared to controls. Contrast 1 was not statistically significant for right or left thalamic area. Contrast 2 was statistically significant and indicated reductions in thalamic area in the patients as compared to controls. The same pattern of results emerged after adjustment for total brain volume. Our results indicate that thalamic abnormalities reported in adult schizophrenic and bipolar patients are also observed in adolescent patients. Our findings also add to the evidence implicating the thalamus in the pathophysiology of schizophrenia and bipolar disorder.