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Funder: Policy Research Unit in Cancer Awareness, Screening and early Diagnosis, PR-PRU-1217-21601, Funder: American Cancer Society NHPDCSGBR-GBRLONG Policy Research Unit in Cancer Awareness, Screening and early Diagnosis, PR-PRU-1217-21601, BACKGROUND: This study investigates whether quantitative breast density (BD) serves as an imaging biomarker for more intensive breast cancer screening by predicting interval, and node-positive cancers. METHODS: This case-control study of 1204 women aged 47-73 includes 599 cancer cases (302 screen-detected, 297 interval; 239 node-positive, 360 node-negative) and 605 controls. Automated BD software calculated fibroglandular volume (FGV), volumetric breast density (VBD) and density grade (DG). A radiologist assessed BD using a visual analogue scale (VAS) from 0 to 100. Logistic regression and area under the receiver operating characteristic curves (AUC) determined whether BD could predict mode of detection (screen-detected or interval); node-negative cancers; node-positive cancers, and all cancers vs. controls. RESULTS: FGV, VBD, VAS, and DG all discriminated interval cancers (all p < 0.01) from controls. Only FGV-quartile discriminated screen-detected cancers (p < 0.01). Based on AUC, FGV discriminated all cancer types better than VBD or VAS. FGV showed a significantly greater discrimination of interval cancers, AUC = 0.65, than of screen-detected cancers, AUC = 0.61 (p < 0.01) as did VBD (0.63 and 0.53, respectively, p < 0.001). CONCLUSION: FGV, VBD, VAS and DG discriminate interval cancers from controls, reflecting some masking risk. Only FGV discriminates screen-detected cancers perhaps adding a unique component of breast cancer risk.

BackgroundOver the past 30 years since the implementation of the National Health Service Breast Screening Programme, improvements in diagnostic techniques and treatments have led to the need for an up-to-date evaluation of its benefit on risk of death from breast cancer. An initial pilot case-control study in London indicated that attending mammography screening led to a mortality reduction of 39%.MethodsBased on the same study protocol, an England-wide study was set up. Women aged 47–89 years who died of primary breast cancer in 2010 or 2011 were selected as cases (8288 cases). When possible, two controls were selected per case (15,202 controls) and were matched by date of birth and screening area.ResultsConditional logistic regressions showed a 38% reduction in breast cancer mortality after correcting for self-selection bias (OR 0.62, 95% CI 0.56–0.69) for women being screened at least once. Secondary analyses by age group, and time between last screen and breast cancer diagnosis were also performed.ConclusionsAccording to this England-wide case-control study, mammography screening still plays an important role in lowering the risk of dying from breast cancer. Women aged 65 or over see a stronger and longer lasting benefit of screening compared to younger women.

Attention-Deficit/Hyperactivity Disorder (ADHD) and Autism Spectrum Disorder (ASD) are associated with motor impairments, with some children holding a comorbid diagnosis of Developmental Coordination Disorder (DCD). However, DCD is underdiagnosed in these populations and the volume abnormalities that contribute to explaining these motor impairments are poorly understood. In this study, motor abilities as measured by the Developmental Coordination Disorder Questionnaire (DCDQ) were compared between children with ADHD, children with ASD and typically developing (TD) children, aged 8-12 years old. Additionally, the association between the DCDQ scores (general coordination, fine motor/handwriting, control during movement, total) and regional volume abnormalities were explored in 6 regions of interest (pre-central gyrus, post-central gyrus, inferior parietal cortex, superior frontal gyrus, middle frontal gyrus, medial frontal gyrus), within each group and across all participants. Children with ASD and children with ADHD showed impaired motor abilities in all the DCDQ-derived scores compared to TD children. Additionally, most children with ASD or ADHD had an indication or suspicion of DCD. Within the ASD group, coordination abilities were associated with the volume of the right medial frontal gyrus, and within the ADHD group, the total DCDQ score was associated with the volume of the right superior frontal gyrus. This study underlines the importance of routinely checking motor abilities in populations with ASD or ADHD in clinical practise and contributes to the understanding of structural abnormalities subtending motor impairments in these disorders., info:eu-repo/semantics/published

Contains fulltext : 232930.pdf (Publisher’s version ) (Closed access) BACKGROUND: On the basis of findings of observational studies and a meta-analysis, proteinuria reduction has been proposed as a surrogate outcome in IgA nephropathy. How long a reduction in proteinuria needs to be maintained to mitigate the long-term risk of disease progression is unknown. METHODS: In this retrospective multiethnic cohort of adult patients with IgA nephropathy, we defined proteinuria remission as a ≥25% reduction in proteinuria from the peak value after biopsy, and an absolute reduction in proteinuria to

International audience; No abstract available

The overlap/distinctiveness between Attention-Deficit/Hyperactivity Disorder (ADHD) and Autism Spectrum Disorder (ASD) has been increasingly investigated in recent years, particularly since the DSM-5 allows the dual diagnosis of ASD and ADHD, but the underlying brain mechanisms remain unclear. Although both disorders are associated with brain volumetric abnormalities, it is necessary to unfold the shared and specific volume abnormalities that could contribute to explain the similarities and differences in the clinical and neurocognitive profiles between ADHD and ASD. In this voxel-based morphometry (VBM) study, regional grey matter volumes (GMV) were compared between 22 children with ADHD, 18 children with ASD and 17 typically developing (TD) children aged 8 to 12 years old, controlling for age and total intracranial volume. When compared to TD children or children with ASD, children with ADHD had a larger left precuneus, and a smaller right thalamus, suggesting that these brain abnormalities are specific to ADHD relative to ASD. Overall, this study contributes to the delineation of disorder-specific structural abnormalities in ADHD and ASD., info:eu-repo/semantics/published

Contains fulltext : 225968.pdf (Publisher’s version ) (Closed access) Immunosuppression in IgA nephropathy (IgAN) should be reserved for patients at high-risk of disease progression, which KDIGO guidelines determine based solely on proteinuria 1g or more/day. To investigate if treatment decisions can be more accurately accomplished using individualized risk from the International IgAN Prediction Tool, we simulated allocation of a hypothetical immunosuppression therapy in an international cohort of adults with IgAN. Two decision rules for treatment were applied based on proteinuria of 1g or more/day or predicted risk from the Prediction Tool above a threshold probability. An appropriate decision was defined as immunosuppression allocated to patients experiencing the primary outcome (50% decline in eGFR or ESKD) and withheld otherwise. The net benefit and net reduction in treatment are the proportion of patients appropriately allocated to receive or withhold immunosuppression, adjusted for the harm from inappropriate decisions, calculated for all threshold probabilities from 0-100%. Of 3299 patients followed for 5.1 years, 522 (15.8%) experienced the primary outcome. Treatment allocation based solely on proteinuria of 1g or more/day had a negative net benefit (was harmful) because immunosuppression was increasingly allocated to patients without progressive disease. Compared to using proteinuria, treatment allocation using the Prediction Tool had a larger net benefit up to 23.4% (95% confidence interval 21.5-25.2%) and a larger net reduction in treatment up to 35.1% (32.3-37.8%). Thus, allocation of immunosuppression to high-risk patients with IgAN can be substantially improved using the Prediction Tool compared to using proteinuria.

Objective: Using Diffusion Tensor Imaging (DTI), to investigate microstructural white matter differences between ADHD and typically developing children (TDC), and their association with inhibition and working memory performance usually impaired in ADHD. Method: Fractional anisotropy (FA) and mean diffusivity (MD) were estimated in 36 noncomorbid children with a Diagnostic and Statistical Manual of Mental Disorders (4th ed., text rev.; DSM-IV-TR) diagnosis of combined type ADHD and 20 TDC. Correlations between FA/MD and Stop Signal Task and N-Back performance parameters were computed. Results: Working memory performance was significantly associated with MD in the superior longitudinal fasciculus (SLF) and the cingulum in the ADHD group. No between-group differences in FA/MD reached significance, after controlling for between-group head motion differences. Conclusion: The association between white matter integrity in the cingulum and the SLF and working memory performance confirms previous studies. Our results also show that when critical conditions are controlled (age, comorbidity, head motion), no ADHD-related structural abnormality (FA/MD) are observed, in line with prior suggestions.

OBJECTIVES: Schizophrenia is a severe psychiatric disease affecting about 1% of the general population. The relative contribution of genetic factors has been estimated to be up to 80%. The mode of inheritance is complex, non-Mendelian, and in most cases involving the combined action of large numbers of genes.METHODS: This review summarises recent efforts to identify genetic variants associated with schizophrenia detected, e.g., through genome-wide association studies, studies on copy-number variants or next-generation sequencing.RESULTS: A large, new body of evidence on genetics of schizophrenia has accumulated over recent years. Many new robustly associated genetic loci have been detected. Furthermore, there is consensus that at least a dozen microdeletions and microduplications contribute to the disease. Genetic overlap between schizophrenia, other psychiatric disorders, and neurodevelopmental syndromes raised new questions regarding the current classification of psychiatric and neurodevelopmental diseases.CONCLUSIONS: Future studies will address especially the functional characterisation of genetic variants. This will hopefully open the doors to our understanding of the pathophysiology of schizophrenia and other related diseases. Complementary, integrated systems biology approaches to genomics, transcriptomics, proteomics and metabolomics may also play crucial roles in enabling a precision medicine approach to the treatment of individual patients.

Adrenomedullin (ADM) regulates vascular tone and endothelial permeability during sepsis. Levels of circulating biologically active ADM (bio-ADM) show an inverse relationship with blood pressure and a direct relationship with vasopressor requirement. In the present prospective observational multinational Adrenomedullin and Outcome in Sepsis and Septic Shock 1 (, AdrenOSS-1) study, we assessed relationships between circulating bio-ADM during the initial intensive care unit (ICU) stay and short-term outcome in order to eventually design a biomarker-guided randomized controlled trial.AdrenOSS-1 was a prospective observational multinational study. The primary outcome was 28-day mortality. Secondary outcomes included organ failure as defined by Sequential Organ Failure Assessment (SOFA) score, organ support with focus on vasopressor/inotropic use, and need for renal replacement therapy. AdrenOSS-1 included 583 patients admitted to the ICU with sepsis or septic shock.Circulating bio-ADM levels were measured upon admission and at day 2. Median bio-ADM concentration upon admission was 80.5 pg/ml [IQR 41.5-148.1 pg/ml]. Initial SOFA score was 7 [IQR 5-10], and 28-day mortality was 22%. We found marked associations between bio-ADM upon admission and 28-day mortality (unadjusted standardized HR 2.3 [CI 1.9-2.9]; adjusted HR 1.6 [CI 1.1-2.5]) and between bio-ADM levels and SOFA score (p0.0001). Need of vasopressor/inotrope, renal replacement therapy, and positive fluid balance were more prevalent in patients with a bio-ADM70 pg/ml upon admission than in those with bio-ADM ≤ 70 pg/ml. In patients with bio-ADM70 pg/ml upon admission, decrease in bio-ADM below 70 pg/ml at day 2 was associated with recovery of organ function at day 7 and better 28-day outcome (9.5% mortality). By contrast, persistently elevated bio-ADM at day 2 was associated with prolonged organ dysfunction and high 28-day mortality (38.1% mortality, HR 4.9, 95% CI 2.5-9.8).AdrenOSS-1 shows that early levels and rapid changes in bio-ADM estimate short-term outcome in sepsis and septic shock. These data are the backbone of the design of the biomarker-guided AdrenOSS-2 trial.ClinicalTrials.gov, NCT02393781 . Registered on March 19, 2015.

International audience; Antibody‐mediated rejection (AMR) that resists to standard of care (SOC) therapy remains a major challenge after kidney transplantation and leads to graft failure in a majority of cases. The use of anti‐IL6 receptor antibodies was suggested to treat chronic antibody‐mediated rejection (cAMR) after failure of classical treatments. We treated nine patients with AMR resistant to apheresis, rituximab, and intravenous immunoglobulins, with a monthly infusion of tocilizumab and compared them with a historical cohort of 37 patients with similar clinical, immunological, and histological characteristics. The 1‐year graft survival and the decline in renal function did not differ between patients who received tocilizumab and those who did not. Histological follow‐up showed that despite a decrease in inflammation and tubulitis scores after tocilizumab, the course of antibody‐mediated lesions and chronic glomerulopathy were similar in both groups. In our study, the addition of monthly infusions of tocilizumab did not alter the course of AMR that resist to SOC therapy. Large randomized studies are urgently needed to assess the effect of tocilizumab in this context.

Objectives. The Val158-allele of the catechol-O-methyltransferase (COMT) Val158Met (rs4680) functional polymorphism has been identified as a risk factor for antisocial behaviour in attention-deficit/hyperactivity disorder (ADHD). Here, we used voxel-based morphometry to investigate the effects of Val158Met polymorphism on grey matter (GM) volumes in a sample of 7–13-year-old children. Methods. MRI and genotype data were obtained for 38 children with combined-type ADHD and 24 typically developing (TD) children. Four regions of interest were identified: striatum, cerebellum, temporal lobe and inferior frontal gyrus (IFG). Results. When compared to TD children, those with ADHD had a significant decrease of GM volume in the IFG. Volume in this region was negatively correlated with ratings of hyperactivity/impulsivity symptoms. Furthermore, the smaller GM volume in the IFG was attributed to the presence of the Met158-allele, as only children with ADHD carrying a Met158-allele exhibited such decrease in the IFG. Children with ADHD homozygotes for the Val158-allele presented increased GM volume in the caudate nucleus when compared with TD children. Conclusions. This study provides the first evidence of a modulation of ADHD-related GM volume alterations by Val158Met in two key regions, possibly mediating the relationship between Val158Met polymorphism and antisocial behaviour in children with ADHD.

Background: Numerous studies have reported associations between the brain-derived neurotrophic factor (BDNF) gene and psychiatric disorders, including suicidal behavior, although with conflicting results. Methods: A total of 250 major depressive disorder patients were collected in the context of a European multicenter resistant depression study and treated with antidepressants at adequate doses for at least 4 weeks. Suicidality was assessed using the Mini International Neuropsychiatric Interview and Hamilton Rating Scale for Depression, and treatment response using the HAM-D. Genotyping was performed for the functional Val66Met polymorphism (rs6265) and 7 additional tagging single nucleotide polymorphisms within the BDNF gene. Results: Neither BDNF single markers nor haplotypes were found to be associated with suicide risk and lifetime history of suicide attempts. Gender-specific analyses revealed nonsignificant single marker (rs908867) and haplotypic association with suicide risk in males after multiple testing correction. Analyzing treatment response phenotypes, the functional Val66Met polymorphism as well as rs10501087 showed significant genotypic and haplotypic association with suicide risk in remitters (n = 34, 13.6%). Conclusions: Considering the sample size, the present findings need to be replicated in larger samples to confirm or refute a role of BDNF in the investigated suicidal behavior phenotypes., SCOPUS: ar.j, info:eu-repo/semantics/published

In the present study, aimed at investigating whether a set of single nucleotide polymorphisms (SNPs) within PTGS2 gene (rs4648276, rs2066826 and rs689466) could be associated with antidepressant response, remission and treatment resistance in a sample of major depression patients, we did not find evidence supporting any of such associations. © 2010 Elsevier Ltd.

Background: In England, population mammographic screening has been offered to women for over 20 years. Overall decrease in breast cancer mortality rates and improvements in cancer awareness and organization of medical care over this period call for a more current evaluation of the mediators behind the better prognosis of screening-exposed breast cancers. Methods: A case–control study was conducted within the English National Breast Screening Program. Women who died from primary breast cancer in 2008 to 2009 were matched (by year of birth, screening invitation, and area) to controls that received a diagnosis of invasive breast cancer at the time of the case diagnosis but survived the case death. Data were analyzed by unconditional logistic regression with adjustment for matching factors. Results: The unadjusted OR for dying from breast cancer associated with ever having attended breast screening was 0.44 [95% confidence interval (CI), 0.33–0.58]. After adjustment for lead time, overdiagnosis, and self-selection, the OR increased to 0.69 (95% CI, 0.50–0.94). Adjusting for tumor size, lymph node status, stage, grade, histopathology, and laterality accounted for all the screening effect (OR, 1.00; 95% CI, 0.71–1.40). Further adjustment for treatment factors only had a minimal impact on the OR (OR, 1.02; 95% CI, 0.72–1.45). Conclusions: Our results suggest that earlier diagnosis, as reflected by tumor characteristics, remains the major mediator of the improvement in breast cancer survival due to participation in mammographic screening. Impact: Mammographic screening continues to prevent breast cancer–related deaths in the epoch of adjuvant systemic therapy. Cancer Epidemiol Biomarkers Prev; 25(3); 479–87. ©2015 AACR. See related article by Massat et al., p. 455

Background: With changes in diagnosis, treatment, and management of breast cancer since the mammography screening trials, there is a need to evaluate contemporary breast screening programs. A case–control study was set up to assess the current impact of attendance in the English Breast Screening Program on breast cancer mortality. Methods: Cancer registry cases who died from primary breast cancer ages 47 to 89 years in London in 2008 to 2009 (869 women) were matched to 1 or 2 general population controls (1,642 women) with no diagnosis of breast cancer at the time of the case's diagnosis, who were alive at the case's death. Cases and controls were matched for date of birth and screening area, and had been invited to breast screening at least once prior to the case's diagnosis. ORs were estimated using conditional logistic regression. Self-selection bias was addressed using contemporaneous attendance at the cervical screening program. Sensitivity analyses were undertaken to assess the likely effect of lead time bias. Results: Attendance at breast screening resulted in a breast cancer mortality reduction of 39% [OR, 0.61; 95% confidence interval (CI), 0.44–0.85] after self-selection correction. Attendance in the last 3 years prior to diagnosis resulted in a 60% mortality reduction (OR, 0.40; 95% CI, 0.31–0.51). Lead time bias effects were negligible. Conclusion: Our results suggest that community breast screening programs provide their expected benefit in terms of reducing the risk of breast cancer death among women participating. Impact: Mammography is an important tool for reducing breast cancer mortality and its impact could be increased by encouraging regular attendance. Cancer Epidemiol Biomarkers Prev; 25(3); 455–62. ©2015 AACR. See related article by Massat et al., p. 479

Cytochrome P450 genes are involved in the metabolism of antidepressants and could influence treatment response. The aim of this study was to investigate the role of allelic variations of the cytochrome P450 CYP1A2, CYP2C9, CYP2C19 and CYP2D6 genes in antidepressant treatment response and remission rates. Two hundred and seventy-eight patients affected by major depression, responders (N=81) and nonresponders (N=197) to at least one adequate antidepressant treatment, were recruited with a multicentre design for resistant depression and genotyped for all relevant variations. None of the considered metabolic profiles (e.g. poor, intermediate, extensive and ultrarapid metabolizers) was found to be associated with either response or remission rates. In conclusion, the investigated cytochrome genes do not seem to play a major role in antidepressant response in the present sample of depressive patients. Nevertheless, methodological and sample size limitations of this study do not allow definitive conclusions. Int Clin Psychopharmacol 24:250-256 (C) 2009 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.

So far, associations between serotonergic neurotransmission pathways and suicidality have been reported. The aim of our study was to investigate the role of genetic polymorphisms and gene-gene interactions of the 5-HTR1A and the 5-HTR2A gene on suicide risk and/or a personal history of suicide attempts. A total of 374 major depressive disorder patients, adequately treated with antidepressants for at least 4 weeks, were collected in the context of a European multicentre study on treatment-resistant depression. We assessed suicidality using the Mini International Neuropsychiatric Interview and the Hamilton Rating Scale for Depression (HAM-D). Treatment response was defined as HAM-D17 and remission as HAM-D7 after 4 weeks of adequate antidepressant treatment. The 5-HTR1A rs6295 (C-1019G) single nucleotide polymorphism (SNP) and the 5-HTR2A rs7997012, rs6313, rs643627 and rs17288723 SNPs were selected for genotyping. Using logistic regression analyses, no association (P

ImportanceAlthough IgA nephropathy (IgAN) is the most common glomerulonephritis in the world, there is no validated tool to predict disease progression. This limits patient-specific risk stratification and treatment decisions, clinical trial recruitment, and biomarker validation. ObjectiveTo derive and externally validate a prediction model for disease progression in IgAN that can be applied at the time of kidney biopsy in multiple ethnic groups worldwide. Design, Setting, and ParticipantsWe derived and externally validated a prediction model using clinical and histologic risk factors that are readily available in clinical practice. Large, multi-ethnic cohorts of adults with biopsy-proven IgAN were included from Europe, North America, China, and Japan. Main Outcomes and MeasuresCox proportional hazards models were used to analyze the risk of a 50% decline in estimated glomerular filtration rate (eGFR) or end-stage kidney disease, and were evaluated using the R-D(2) measure, Akaike information criterion (AIC), C statistic, continuous net reclassification improvement (NRI), integrated discrimination improvement (IDI), and calibration plots. ResultsThe study included 3927 patients; mean age, 35.4 (interquartile range, 28.0-45.4) years; and 2173 (55.3%) were men. The following prediction models were created in a derivation cohort of 2781 patients: a clinical model that included eGFR, blood pressure, and proteinuria at biopsy; and 2 full models that also contained the MEST histologic score, age, medication use, and either racial/ethnic characteristics (white, Japanese, or Chinese) or no racial/ethnic characteristics, to allow application in other ethnic groups. Compared with the clinical model, the full models with and without race/ethnicity had better R-D(2) (26.3% and 25.3%, respectively, vs 20.3%) and AIC (6338 and 6379, respectively, vs 6485), significant increases in C statistic from 0.78 to 0.82 and 0.81, respectively (Delta C, 0.04; 95% CI, 0.03-0.04 and Delta C, 0.03; 95% CI, 0.02-0.03, respectively), and significant improvement in reclassification as assessed by the NRI (0.18; 95% CI, 0.07-0.29 and 0.51; 95% CI, 0.39-0.62, respectively) and IDI (0.07; 95% CI, 0.06-0.08 and 0.06; 95% CI, 0.05-0.06, respectively). External validation was performed in a cohort of 1146 patients. For both full models, the C statistics (0.82; 95% CI, 0.81-0.83 with race/ethnicity; 0.81; 95% CI, 0.80-0.82 without race/ethnicity) and R-D(2) (both 35.3%) were similar or better than in the validation cohort, with excellent calibration. Conclusions and RelevanceIn this study, the 2 full prediction models were shown to be accurate and validated methods for predicting disease progression and patient risk stratification in IgAN in multi-ethnic cohorts, with additional applications to clinical trial design and biomarker research.

Item does not contain fulltext The Oxford Classification of IgA nephropathy (IgAN) includes the following four histologic components: mesangial (M) and endocapillary (E) hypercellularity, segmental sclerosis (S) and interstitial fibrosis/tubular atrophy (T). These combine to form the MEST score and are independently associated with renal outcome. Current prediction and risk stratification in IgAN requires clinical data over 2 years of follow-up. Using modern prediction tools, we examined whether combining MEST with cross-sectional clinical data at biopsy provides earlier risk prediction in IgAN than current best methods that use 2 years of follow-up data. We used a cohort of 901 adults with IgAN from the Oxford derivation and North American validation studies and the VALIGA study followed for a median of 5.6 years to analyze the primary outcome (50% decrease in eGFR or ESRD) using Cox regression models. Covariates of clinical data at biopsy (eGFR, proteinuria, MAP) with or without MEST, and then 2-year clinical data alone (2-year average of proteinuria/MAP, eGFR at biopsy) were considered. There was significant improvement in prediction by adding MEST to clinical data at biopsy. The combination predicted the outcome as well as the 2-year clinical data alone, with comparable calibration curves. This effect did not change in subgroups treated or not with RAS blockade or immunosuppression. Thus, combining the MEST score with cross-sectional clinical data at biopsy provides earlier risk prediction in IgAN than our current best methods.

Female participants have been underrepresented in previous structural magnetic resonance imaging reports on attention-deficit/hyperactivity disorder (ADHD). In this study, we used optimized voxel-based morphometry to examine grey matter volumes in a sample of 33 never-medicated children with combined-type ADHD and 27 typically developing (TD) children. We found a gender-by-diagnosis interaction effect in the ventral anterior cingulate cortex (ACC), whereby boys with ADHD exhibited reduced volumes compared with TD boys, while girls with ADHD showed increased volumes when compared with TD girls. Considering the key role played by the ventral ACC in emotional regulation, we discuss the potential contribution of these alterations to gender-specific symptoms' profiles in ADHD., SCOPUS: ar.j, info:eu-repo/semantics/published

Purpose: Mood disorders are present in more than 90% of suicides, and a genetic vulnerability to suicidality is well established. Numerous lines of evidence relate the transcription factor Cyclic adenosine monophosphate Response Element Binding protein (CREB1) to suicide, and to the aetiology of major depressive disorder (MDD). Our aim was to test for association between CREB1 single nucleotide polynnorphisms (SNPs) and both suicide risk (SR) and a personal history of suicide attempt (SA) in MDD patients. Materials and Methods: A sample of 250 MDD patients collected in the context of a European multicenter resistant depression study and treated with antidepressants over a period of at least 4 weeks were genotyped for five CREB1 SNPs (rs2709376, rs2253206, rs7569963, rs7594560, and rs4675690). To assess suicidality, the Mini International Neuropsychiatric Interview (MINI) and the Hamilton Rating Scale for Depression (HAM-D) were applied. Results: Neither single-marker nor haplotypic association were found between SR and/or a personal history of SA with any of the investigated SNPs after multiple testing correction. For females, an association between rs2709376 and a personal history of SA was found (p = 0.016), however not resisting multiple testing correction. Conclusions: Although we found significant CREB1 single marker association with a personal history of SA in female MDD patients, this finding could not be confirmed in haplotypic analyses after multiple testing correction. Larger well-defined cohorts are required to confirm or refute a possible association of CREB1 and SA in female MDD patients.

Osteoarthritis (OA) is a major cause of long-term disability (1). Traditionally characterized by structural degradation of one or more synovial joints, OA is typically associated with pain, swelling, and stiffness (2). Reduced manual dexterity and inability to perform tasks due to symptoms affect quality of life and ability to function independently (3). Levels of pain and disability experienced by patients often do not correspond to the level of tissue damage observed in the affected joints (4), suggesting involvement of central nervous system mechanisms in the generation of OA-related pain (5). Given the prevalence of OA and an increasingly aging population, there is a pressing need for more effective treatments (6,7). Many commonly prescribed medications are ill suited for long-term use due to side effects including tolerance, dependency, and gastrointestinal complications (8,9). While pain is always a personal experience and subject to multiple psychosocial factors, there has long been a desire to complement subjective reports with reliable markers of pain perception and treatment effectiveness (10,11). Neuroimaging methodologies offer the potential to meet these desires (12). Functional magnetic resonance imaging (fMRI) provides a safe, noninvasive, repeatable indirect measure of neural activity suitable for use in crossover trial designs (12). Reports have suggested that fMRI could demonstrate analgesic effects in populations of patients with clinical pain, adding value to conventional behavioral end points and facilitating decision-making early in drug development, reducing risk, development times, and cost (12). Experimental fMRI studies have provided useful insights into the neural mechanisms of drug action (for review, see ref.(13)). In order to fulfill this potential, fMRI must depict the neural correlates of the response to analgesics in patients experiencing persistent pain. Preliminary studies in OA have shown promise in establishing neural correlates of response to analgesics (14,15), but to date these studies have been underpowered or lacked appropriate placebo control. In this study we investigated the potential of fMRI as a “fit-for-purpose” measurement technique in development of analgesics for persistent pain. We sought to determine the ability of fMRI to detect changes in brain functioning following a 1-week course of naproxen in individuals with OA of the first carpometacarpal (CMC) joint. Naproxen is an established, effective nonsteroidal antiinflammatory drug (NSAID) labeled for treatment of OA-related symptoms in the UK (http://www.emc.medicines.org.uk). We aimed to detect naproxen-induced changes in brain activity using a functionally relevant task that evoked pain. We hypothesized that task-evoked brain activity would be reduced following administration of naproxen, compared to placebo. In particular, we hypothesized that a network of brain regions previously associated with pain perception would display significant reductions in activity following naproxen administration, during the task load that induced the highest rating of pain intensity.

Dodecafluoropentane emulsion (DDFPe) is a novel nanotechnology for oxygen delivery with therapeutic potential for hemorrhagic shock and/or traumatic brain injury (TBI). DDFPe demonstrates efficacy at smaller doses than previously tested perfluorocarbon oxygen therapeutics. This smaller dose potentially eliminates toxicities exhibited by previous oxygen therapeutics, whereas anti-inflammatory properties of DDFPe may alleviate damage from ischemia reperfusion injury. This minireview summarizes our progress in developing a battlefield-ready product to prevent combat death due to hemorrhagic shock and/or TBI. Preclinical studies, for both indications, show promising effects of DDFPe as a resuscitation fluid. DDFPe may become a part of the toolkit for tactical healthcare professionals in battlefield and domestic emergency medicine.

Mammographic density is a strong risk factor for breast cancer, but its potential application in risk management is not clear, partly due to uncertainties about its interaction with other breast cancer risk factors. We aimed to quantify the impact of mammographic density on breast cancer risk in women aged 40-49 at intermediate familial risk of breast cancer (average lifetime risk of 23%), in particular in premenopausal women, and to investigate its relationship with other breast cancer risk factors in this population. We present the results from a case-control study nested with the FH01 cohort study of 6,710 women mostly aged 40-49 at intermediate familial risk of breast cancer. One hundred and three cases of breast cancer were age-matched to one or two controls. Density was measured by semiautomated interactive thresholding. Absolute density, but not percent density, was a significant risk factor for breast cancer in this population after adjusting for area of nondense tissue (OR per 10 cm(2) = 1.07, 95% CI 1.00-1.15, p = 0.04). The effect was stronger in premenopausal women, who made up the majority of the study population. Absolute density remained a significant predictor of breast cancer risk after adjusting for age at menarche, age at first live birth, parity, past or present hormone replacement therapy, and the Tyrer-Cuzick 10-year relative risk estimate of breast cancer. Absolute density can improve breast cancer risk stratification and delineation of high-risk groups alongside the Tyrer-Cuzick 10-year relative risk estimate.

Women with a genetic predisposition to breast cancer tend to develop the disease at a younger age with denser breasts making mammography screening less effective. The introduction of magnetic resonance imaging (MRI) for familial breast cancer screening programs in recent years was intended to improve outcomes in these women. We aimed to assess whether introduction of MRI surveillance improves 5- and 10-year survival of high-risk women and determine the accuracy of MRI breast cancer detection compared with mammography-only or no enhanced surveillance and compare size and pathology of cancers detected in women screened with MRI + mammography and mammography only. We used data from two prospective studies where asymptomatic women with a very high breast cancer risk were screened by either mammography alone or with MRI also compared with BRCA1/2 carriers with no intensive surveillance. 63 cancers were detected in women receiving MRI + mammography and 76 in women receiving mammography only. Sensitivity of MRI + mammography was 93 % with 63 % specificity. Fewer cancers detected on MRI were lymph node positive compared to mammography/no additional screening. There were no differences in 10-year survival between the MRI + mammography and mammography-only groups, but survival was significantly higher in the MRI-screened group (95.3 %) compared to no intensive screening (73.7 %; p = 0.002). There were no deaths among the 21 BRCA2 carriers receiving MRI. There appears to be benefit from screening with MRI, particularly in BRCA2 carriers. Extended follow-up of larger numbers of high-risk women is required to assess long-term survival.

Dopamine active transporter gene (DAT1) is a candidate gene associated with attention-deficit/hyperactivity disorder (ADHD). The DAT1 variable number tandem repeat (VNTR)-3' polymorphism is functional and 9R carriers have been shown to produce more DAT than 10R homozygotes. We used functional magnetic resonance imaging (fMRI) to investigate the effects of this polymorphism on the neural substrates of working memory (WM) in a small but selected population of children with ADHD, naïve of any psychotropic treatment and without comorbidity. MRI and genotype data were obtained for 36 children (mean age: 10,36 +/- 1,49 years) with combined-type ADHD (9R n = 15) and 25 typically developing children (TDC) (mean age: 9,55 +/- 1,25 years) (9R n = 12). WM performance was similar between conditions. We found a cross-over interaction effect between gene (9R vs. 10R) and diagnosis (TDC vs. ADHD) in the orbito-frontal gyrus, cerebellum and inferior temporal lobe. In these areas, WM-related activity was higher for 9R carriers in ADHD subjects and lower in TDC. In ADHD children only, 10R homozygotes exhibited higher WM-related activity than 9R carriers in a network encompassing the parietal and the temporal lobes, the ventral visual cortex, the orbito-frontal gyrus and the head of the caudate nucleus. There was no significant results in TDC group. Our preliminary findings suggest that DAT1 VNTR polymorphism can modulate WM-related brain activity ADHD children., SCOPUS: ar.j, info:eu-repo/semantics/published

Treatment resistant depression (TRD) is a significant clinical and public health problem. Among others, neuroplasticity and inflammatory pathways seem to play a crucial role in the pathomechanisms of antidepressant efficacy. The primary aim of this study was to investigate whether a set of single nucleotide polymorphisms (SNPs) within two genes implicated in neuroplasticity and inflammatory processes (the mitogen activated protein kinase 1, MAPK1 (rs3810608, rs6928, rs13515 and rs8136867), and the cyclic AMP responsive element binding protein 1, CREB1 (rs889895, rs6740584, rs2551922 and rs2254137)) was associated with antidepressant treatment resistance (according to two different definitions), in 285 Major Depressive Disorder (MDD) patients. As secondary aims, we investigated the genetic modulation of the same SNPs on response, remission and other clinical features both in MDD patients and in a larger sample including 82 Bipolar Disorder (BD) patients as well. All patients were screened in the context of a European multicenter project. No association between both the investigated genes and treatment resistance and response was found in MDD patients. However, considering remission, higher rates of CREB1 rs889895 GG genotype were reported in MDD patients. Moreover, MAPK1 rs8136867 AG genotype was found to be associated with remission in the whole sample (MDD and BD). Present results suggest that some genetic polymorphisms in both GREW and MAPK1 could be associated with treatment remission. Although further research is needed to draw more definitive conclusions, such results are intriguing since suggest a potential role of two genes implicated in neuroplasticity and inflammatory processes in symptom remission after antidepressant treatment. (C) 2013 Elsevier Inc. All rights reserved.

The available data from preclinical and pharmacological studies on the role of the C-O-methyl transferase (COMT) support the hypothesis that abnormal catecholamine transmission has been implicated in the pathogenesis of mood disorders (MD). We examined the relationship of a common functional polymorphism (Val108/158Met) in the COMT gene, which accounts for four-fold variation in enzyme activity, with 'early-onset' (EO) forms (less than or equal to 25 years) of MD, including patients with major depressive disorder (EO-MDD) and bipolar patients (EO-BPD), in a European multicenter case-control sample. Our sample includes 378 MDD (120 EO-MDD), 506 BPD (222 EO-BPD) and 628 controls. An association was found between the high-activity COMT Val allele, particularly the COMT Val/Val genotype and EO-MDD. These findings suggest that the COMT Val/Val genotype may be involved in EO-MDD or may be in linkage disequilibrium with a different causative polymorphism in the vicinity. The COMT gene may have complex and pleiotropic effects on susceptibility and symptomatology of neuropsychiatric disorders.

Recently published data have reported associations between cytochrome P450 metabolizer status and suicidality. The aim of our study was to investigate the role of genetic polymorphisms of the cytochrome P450 genes on suicide risk and/or a personal history of suicide attempts. Two hundred forty-three major depressive disorder patients were collected in the context of a European multicentre resistant depression study and treated with antidepressants at adequate doses for at least 4 weeks. Suicidality was assessed using the Mini International Neuropsychiatric Interview and the Hamilton Rating Scale for Depression (HAM-D). Treatment response was defined as HAM-D a parts per thousand currency sign 17 and remission as HAM-D a parts per thousand currency sign 7 after 4 weeks of treatment with antidepressants at adequate dose. Genotyping was performed for all relevant variations of the CYP1A2 gene (*1A, *1F, *1C, *1 J, *1 K), the CYP2C9 gene (*2, *3), the CYP2C19 gene (*2, *17) and the CYP2D6 gene (*3, *4, *5, *6, *9, *19, *XN). No association between both suicide risk and personal history of suicide attempts, and the above mentioned metabolic profiles were found after multiple testing corrections. In conclusion, the investigated cytochrome gene polymorphisms do not seem to be associated with suicide risk and/or a personal history of suicide attempts, though methodological and sample size limitations do not allow definitive conclusions.

Inflammatory pathways play a crucial role in the pathomechanisms of antidepressant efficacy. The aim of this study was to investigate whether a set of single nucleotide polymorphisms (SNPs) within cyclooxygenase-2 (COX-2, rs5275 and rs20417) and oxytocin receptor (OXTR, rs53576 and rs2254298) genes was associated with antidepressant treatment resistance, response or remission. Three hundred seventy-two patients were recruited in the context of a multicenter resistant depression study. They were genotyped for COX-2 and OXTR SNPs. Treatment resistance (according to two different definitions), response and remission were recorded. We did not observe any association between the genotypes or alleles of the selected SNPs within COX-2 and OXTR genes and treatment resistance, response and remission in the whole sample. Our results are consistent with those of some studies but not with those of other ones. Indeed, several factors could be involved in the discrepancy observed across studies. They include sample size, environmental factors, differences in ethnicity, different study designs, and different definitions of treatment resistance. (C) 2012 Elsevier Ireland Ltd. All rights reserved.

In the present study, we aimed to confirm the previous finding of an association between GRIK4 and GNB3 variants (rs195478 and rs5443) and remission and treatment resistance in major depression, using a multicenter sample of 223 patients. We did not find any supporting evidence for such associations. These conflicting data may result from difficulties in the replication of candidate gene association studies.

Objective: The management of treatment-resistant depression is a much debated issue. In particular, the evidence supporting the commonly suggested sequential use of antidepressants from 2 different pharmacological classes is weak.This retrospective study was undertaken to investigate whether there is a better response in nonresponders switched to a different class of antidepressants (across-class) compared with nonresponders switched to an antidepressant from the same class (within-class). Methods: Three hundred forty patients with primary major depressive disorder were recruited in the context of a European multicenter project. Subjects whose current depressive episode had failed to respond to a first antidepressant trial of adequate dose and duration were included. Results: There was no significant difference in response or remission rates between the across-class and within-class groups after controlling for possible confounders. Conclusions: In depressed nonresponders to a previous antidepressant treatment, switching to a different class of antidepressants was not associated with a better response or remission rate. © 2011 Lippincott Williams & Wilkins.

Hemoglobin-based oxygen carrier-201 (HBOC) was developed as a resuscitative fluid but concerns exist over potentially adverse vasoconstriction. This study evaluated whether concurrent IV (intra venous) N-acetyl-L-cysteine (NAC) or hyaluronic acid (HA) would attenuate HBOC-associated vasoconstriction, assessed by systemic blood pressures and cerebral pial microvasculature, when administered to healthy, anesthetized rats. Rats (8-9/group) received a 30 min infusion of 3 ml/kg HBOC, HBOC plus 600 mg/kg NAC (HBOC/NAC), HBOC plus 1.5 mg/kg HA (HBOC/HA) or 3 ml/kg Albumin. Mean (MAP) and systolic (SBP) blood pressures, blood chemistries and cerebral pial vessel diameters were measured at baseline, end of infusion, and intermittently for an additional 90 min. HBOC caused immediate and sustained increases in SBP and MAP (35.3 ± 3.6 and 29.1 ± 2.5 mm Hg peak increases above baseline, respectively; mean ± SEM) and immediate but progressive vasoconstriction (11 µm maximum reduction) in medium-sized (50-100 µm) pial arterioles. When NAC was co-administered, blood pressure changes were attenuated and vessel changes were abolished. Similar trends were noted with co-administration of HA but were not statistically different from HBOC-alone. Small-sized (< 50 µm) pial vessels and blood parameters showed no differences from baseline or among groups. No adverse clinical signs were observed. We demonstrated that it is possible for adjuvant drugs to reduce the vasoconstriction associated with HBOC-201. Coinfusion of the anti-oxidant NAC mitigated HBOC-201-associated increases in blood pressures and vasoconstriction in medium-sized cerebral pial vessels. The drag-reducing polymer HA may be more effective at a higher dose as a similar but non-significant trend was observed.

This study compares behavioral and electrophysiological (P300) responses recorded in a cued continuous performance task (CPT-AX) performed by children with attention deficit hyperactivity disorder-combined subtype (ADHD-com) and age-matched healthy controls. P300 cognitive-evoked potentials and behavioral data were recorded in eight children with ADHD (without comorbidity) and nine control children aged 8-12 years while performing a CPT-AX task. Such task enables to examine several kinds of false alarms and three different kinds of P300 responses: the "Cue P300", the "Go P300" and the "NoGo P300", respectively, associated with preparatory processing/attentional orienting, motor/response execution and motor/response inhibition. Whereas hit rates were about 95% in each group, ADHD children made significantly more false alarm responses (inattention- and inhibition-related) than control children. ADHD children had a marginally smaller Cue P300 than the control children. Behavioral and electrophysiological findings both highlighted inhibition and attention deficits in ADHD-com children in the CPT-AX task. A rarely studied kind of false alarm, the "Other" FA, seems to be a sensitive FA to take into account, even if its interpretation remains unclear.

Objectives. Evidence in favour of switching between selective serotonin reuptake inhibitor (SSRI) and tricyclic (TCA) antidepressants in treatment resistant depression has been tested in a few studies only, consequently a prospective study was undertaken to evaluate the impact of switching strategies. Methods. One hundred eighty-nine patients who failed to respond to a previous antidepressant were randomised to four arms: firstly they received citalopram or desipramine for a 4-week period; secondly, those who failed to respond were treated for a further 4-week period with the same antidepressant (citalopram-citalopram and desipramine-desipramine arms) or switched to the alternate one (citalopram-desipramine and desipramine-citalopram arms). Results. There was no difference in the first 4-week phase between patients receiving citalopram versus desipramine in Hamilton Rating Scale for Depression (HRSD), Montgomery--Asberg Depression Rating Scale (MADRS), and Clinical Global Impression (CGI) scores. In the second 4-week phase remitter rates were higher among non-switched patients (P == 0.04). Moreover, considering HRSD and MADRS, switched patients reported significantly higher scores (P < a parts per thousand currency sign 0.02 for both scales at each time-point). Conclusions. This study supports the thesis that switching from an SSRI to a TCA (and vice versa) in non-responders to a 4-week trial of an SSRI/TCA is not associated with improved response. The result goes in the opposite direction to that predicted by current guidelines.

Background: The transcription factor Cyclic adenosine monophosphate Response Element Binding (CREB) protein has been repeatedly involved in the aetiology and pharmacotherapy of major depression (MD). The aim of this study was to investigate the potential association of a set of single nucleotide polymorphisms (SNPs) in CREB1 gene and both MD and response, remission and treatment resistance to antidepressants. Methods: One hundred-ninety MD patients collected in the context of a resistant depression study and treated with antidepressants for at least 4 weeks were genotyped for 5 CREB1 SNPs (rs2709376, rs2253206, rs7569963, rs7594560, and rs4675690). Response, remission and treatment resistance were recorded. Results: An allele of rs7569963 as well as rs2253206-rs7569963 A-A and rs7569963-rs4675690 A-C haplotypes were associated with the status of treatment resistance. Additionally, rs7569963 GG genotype was positively associated with remission. No further significant associations were observed. Limitations: Limitations of the present study include a relatively small sample size and the incomplete ascertainment of data which could influence the outcome. Conclusions: Our results preliminary suggest that some genetic polymorphisms in CREB1 could be associated to treatment resistance. Although such finding needs to be replicated in larger samples, it increases current knowledge about the genetic predictors of response to antidepressants that will probably lead to enhance treatment outcomes by addressing each individual to the most appropriate treatment strategy in the early stages of treatment. (C) 2010 Elsevier B.V. All rights reserved.

Our study aims at replicating our previous finding of an association between COMT rs4680 G/A polymorphism and early onset major depression (MD). We included 462 MD, 147 bipolar disorders (BD) subjects and 295 healthy controls. We could partially replicate previous findings. In particular, rs4680 GG + AG genotypes were more represented in the subgroup of early onset MD patients (p = 0.04). Additionally, we observed an association between rs737865 alleles and early onset MD (p = 0.04). Rs4680 genotype was associated with early onset BD as well (p = 0.01). In conclusion, we partially replicated our previous findings confirming a possible influence of COMT variants in MD and BD, particularly in early onset subjects, though not with the same risk genotypes. (C) 2011 Elsevier Ireland Ltd. All rights reserved.

In a previous dose escalation study our group found that combining 90μg/kg rFVIIa with HBOC-201 reduced blood loss and improved physiologic parameters compared to HBOC alone. In this follow-up study in a swine liver injury model, we found that while there were no adverse hematology effects and trends observed in the previous study were confirmed, statistical significance could not be reached. Additional pre-clinical studies are indicated to identify optimal components of a multifunctional blood substitute for clinical use in trauma.

Vasoconstriction is a major adverse effect of first and second generation hemoglobin-based oxygen carriers (HBOCs) that hinders their development as blood substitute. However, intravenous infusion of HBOC-201 (second generation) to patients induces significant pulmonary hypertension without significant coronary vasoconstriction. We compared contractile responses of isolated bovine pulmonary and coronary arterial strips to HBOC-201 and HBOC-205LL.LT.MW600 (third generation), polymerized bovine hemoglobins of different molecular weight, and their attenuation by nitroglycerin, sodium nitroprusside (SNP), and sodium nitrite. Pulmonary arteries developed negligible basal tone, but exhibited HBOC-dependent amplification of phenylephrine-induced contractions. In contrast, coronary arteries developed significant basal tone, and exhibited HBOC-dependent constant force increment to serotonin-induced contractions. Therefore, relative to basal tone, HBOC-induced contractions were greater in pulmonary than coronary arteries. Furthermore, HBOC-205LL.LT.MW600 appeared to be less vasoactive than HBOC-201. Unexpectedly, pulmonary and coronary arteries exhibited differential sensitivities to nitrovasodilators in parallel with their differential sensitivities to HBOC. However, SNP and sodium nitrite induced significant methemoglobin formation from HBOC, whereas nitroglycerin did not. These results suggest that phenotypic differences between pulmonary and coronary vascular smooth muscle cells could explain the differential hypertensive effects of HBOC on pulmonary and coronary circulation in patients. Among the three nitrovasodilators investigated, nitroglycerin appears to be the most promising candidate for attenuating HBOC-induced pulmonary hypertension in older HBOCs.

In consenting Jehovah's Witness patients and others for whom blood is contraindicated or not available, hemoglobin-based oxygen carrier (HBOC)-201 may enable survival in acutely anemic patients while underlying conditions are treated.Survival factors were identified in a multicenter, unblinded series of severely anemic "compassionate use" patients receiving available standard treatment plus consultant-supported HBOC-201 administration by novice users. Predictors of outcome were sought and compared between survivors and nonsurvivors. A compound variable, hemoglobin-duration deficit product was used to describe the interactive clinical effects of severity and duration of anemia. Mortality,correlations between patient characteristics, and survival to hospital discharge were determined from patient records.Fifty-four patients (median age 50 years) with life-threatening anemia (median hemoglobin concentration at time of request = 4 g/dL) received 60 to 300 g HBOC-201.Twenty-three patients (41.8%) were discharged. Intraoperative blood loss (45%), malignancy(18%), and acute hemolysis (13%) were the prevailing reasons for anemia. Time from onset of anemia (or = 8 g/dL) to HBOC-201 infusion was shorter for survivors than nonsurvivors (3.2 vs 4.4 days, P = 0.027). Mean hemoglobin levels before HBOC-201 infusion in survivors and nonsurvivors were 4.5 and 3.8 g/dL, respectively (P = 0.120). No serious adverse event was attributed to HBOC-201. The hemoglobin-duration deficit product separated survivors from nonsurvivors. Cancer and renal disease were associated with nonsurvival.Earlier, compared with later, administration by inexperienced users of HBOC-201 to patients with anemia was associated with improved chances of survival of acutely bleeding and hemolyzing patients. Survival was more likely if the duration and magnitude of low hemoglobin was minimized before treatment with HBOC-201.

Summary Background & aims Outcomes of anorexia nervosa in patients meeting criteria for hospitalization were compared to those treated as outpatients. Methods A questionnaire on the quality of recovery was completed by 143 patients. Groups were defined according to indication for hospitalization during the first 6 months of care (inpatient treatment: n = 46, ambulatory treatment: n = 97). Results At intake, inpatients were characterized by lower BMI, and by higher prevalence of restrictive forms of the disease and prior suicide attempts. After 5 year follow-up, outcomes were similar in inpatients and outpatients respectively for BMI (18.4 vs. 19.2 kg/m 2 ), frequency of BMI normalization (45.7 vs. 49%), self reports of feeling “completely cured” (21% in both), educational attainment and professional functioning. Amenorrhea was more frequent in inpatients (21.7% vs. 8.2%). Inpatients also more frequently continued under medical supervision at the time of this study. Conclusions Despite a more severe initial presentation, patients requiring hospitalization at entry exhibited outcomes comparable to outpatients, although requiring longer care.

There is little agreement on what constitutes remission in anorexia nervosa.This study compared the medical, psychological, and social status of 2 female populations previously treated for anorexia nervosa and differing in their achievement of normal weight.One hundred forty-one patients responded to a questionnaire documenting morphometric parameters, subjective perception of outcome, concerns about body shape and diet, and quality of familial, emotional, and professional life. Two groups were defined according to body mass index (BMI): normal (n = 69) with BMIor = 18.5 kg/m(2), and subnormal (n = 72) with BMI18.5 kg/m(2). In addition, subgroups (21 in each category) were interviewed. An age-matched control population composed of 156 women, either students or Health Services employees, responded to a similar questionnaire.Only a minority of patients assessed themselves as recovered, and there was no statistically significant difference in perception of recovery between normal BMI and subnormal BMI groups (27.5% and 15.3%, respectively). As expected, underweight patients reported significantly more frequent purging behaviors, amenorrhea, recent hospitalization, and prolonged student status. In contrast, there were no significant differences in terms of pregnancy rate, psychiatric comorbidities, social integration, sexual activity, and self-assessment of professional and familial life. In comparison to control subjects, former anorexia patients with normalized BMI more frequently reported vomiting, fear of high-calorie foods, and treatment for depression.These few long-term advantages observed after BMI normalization suggest that normalization of nutritional status remains an important target in anorexia nervosa. However, the persistence of psychological distress after nutritional recovery confirms that more effective treatments are needed that target long-term psychological recovery.

Dr. Berrino raises the possibility of a healthy screenee bias in our estimates of the effect of being screened between 3 and 36 months before diagnosis and of ever being screened ([1, 2][1]). The argument for the presence of such bias hangs on the exclusion of the 3-month period before diagnosis and

Genetic deletion of brain serotonin (5-HT) neurons in mice leads to ventilatory deficits and increased neonatal mortality during development. However, it is unclear if the loss of the 5-HT neurons or the loss of the neurochemical 5-HT led to the observed physiologic deficits. Herein, we generated a mutant rat model with constitutive central nervous system (CNS) 5-HT depletion by mutation of the tryptophan hydroxylase 2 ( Tph2) gene in dark agouti (DATph2−/−) rats. DATph2−/−rats lacked TPH immunoreactivity and brain 5-HT but retain dopa decarboxylase-expressing raphe neurons. Mutant rats were also smaller, had relatively high mortality (∼50%), and compared with controls had reduced room air ventilation and body temperatures at specific postnatal ages. In adult rats, breathing at rest and hypoxic and hypercapnic chemoreflexes were unaltered in adult male and female DATph2−/−rats. Body temperature was also maintained in adult DATph2−/−rats exposed to 4°C, indicating unaltered ventilatory and/or thermoregulatory control mechanisms. Finally, DATph2−/−rats treated with the 5-HT precursor 5-hydroxytryptophan (5-HTP) partially restored CNS 5-HT and showed increased ventilation ( P < 0.05) at a developmental age when it was otherwise attenuated in the mutants. We conclude that constitutive CNS production of 5-HT is critically important to fundamental homeostatic control systems for breathing and temperature during postnatal development in the rat.

Background Atherosclerotic renal artery stenosis (ARAS) activates oxidative stress and chronic inflammatory injury. Contrast imaging and endovascular stenting pose potential hazards for acute kidney injury, particularly when superimposed upon reduced kidney perfusion. Methods We measured sequential early and long-term changes in circulating inflammatory and injury biomarkers in 12 ARAS subjects subjected to computed tomography imaging and stent revascularization compared with essential hypertensive (EH) subjects of similar age under fixed sodium intake and medication regimens in a clinical research unit. Results NGAL, TIMP-2, IGFBP7, MCP-1 and TNF-α all were elevated before intervention. Post-stenotic kidney volume, perfusion, blood flow and glomerular filtration rate (GFR) were lower in ARAS than in EH subjects. TIMP-2 and IGFBP7 fell briefly, then rose over 18 h after contrast imaging and stent deployment. Circulating NGAL decreased and remained lower for 27 h. These biomarkers in ARAS returned to baseline after 3 months, while kidney volume, perfusion, blood flow and GFR increased, but remained lower than EH. Conclusions These divergent patterns of inflammatory signals are consistent with cell cycle arrest (TIMP-2, IGFBP7) and relative protection from acute kidney injury after imaging and stenting. Sustained basal elevation of circulating and renal venous inflammatory biomarkers support ongoing, possibly episodic, renal stress in ARAS that limits toxicity from stent revascularization.

While perfluorocarbons (PFCs) may be useful in some clinical situations, previous studies have shown that interferences with chemistry analytes can occur with blood samples containing PFCs. This in vitro study focused on how the PFC Oxycyte may affect hematology measurements in blood samples. Swine blood diluted with Oxycyte or saline (Controls) were analyzed for Hemoglobin (Hb), Mean Corpuscular Volume (MCV),Hematocrit (Hct) and Fluorocrit (Fct) using a HemaVet, ABL-735 (ABL), or microhematocrit. Ancillary tests (blood viscosity, electrolytes, cell counts, and red blood cell morphology) were performed secondarily. Increasing Oxycyte resulted in increases in MCV, Hct, and visible cell shape change and morphology vs. Controls. Effects correlated with lower sodium in Oxycyte samples vs. Controls. With increasing Oxycyte, Hb became higher than Controls or became unpredictable depending on the instrument (HemaVet or ABL, respectively). Fct was smaller than predicted and likely represented the heaviest components of Oxycyte. At ≥50 % Oxycyte, RBC hemolysis rendered further measurements impractical. Viscosity first increased then decreased with increasing Oxycyte, peaking at ~40 % Oxycyte. Hct, MCV, Hb, and RBC morphology may be affected by Oxycyte. These observations correlated with lower sodium and increasing Oxycyte, causing hemolysis at high Oxycyte concentrations. These changes were due to alterations in the blood samples in vitro and this should be considered when interpreting hematology parameters from in vivo studies.

Purpose: Noninvasive biomarkers for early detection of pancreatic ductal adenocarcinoma (PDAC) are currently not available. Here, we aimed to identify a set of urine proteins able to distinguish patients with early-stage PDAC from healthy individuals. Experimental design: Proteomes of 18 urine samples from healthy controls, chronic pancreatitis, and patients with PDAC (six/group) were assayed using GeLC/MS/MS analysis. The selected biomarkers were subsequently validated with ELISA assays using multiple logistic regression applied to a training dataset in a multicenter cohort comprising 488 urine samples. Results: LYVE-1, REG1A, and TFF1 were selected as candidate biomarkers. When comparing PDAC (n = 192) with healthy (n = 87) urine specimens, the resulting areas under the receiver-operating characteristic curves (AUC) of the panel were 0.89 [95% confidence interval (CI), 0.84–0.94] in the training (70% of the data) and 0.92 (95% CI, 0.86–0.98) in the validation (30% of the data) datasets. When comparing PDAC stage I–II (n = 71) with healthy urine specimens, the panel achieved AUCs of 0.90 (95% CI, 0.84–0.96) and 0.93 (95% CI, 0.84–1.00) in the training and validation datasets, respectively. In PDAC stage I–II and healthy samples with matching plasma CA19.9, the panel achieved a higher AUC of 0.97 (95% CI, 0.94–0.99) than CA19.9 (AUC = 0.88; 95% CI, 0.81–0.95, P = 0.005). Adding plasma CA19.9 to the panel increased the AUC from 0.97 (95% CI, 0.94–0.99) to 0.99 (95% CI, 0.97–1.00, P = 0.04), but did not improve the comparison of stage I–IIA PDAC (n = 17) with healthy urine. Conclusions: We have established a novel, three-protein biomarker panel that is able to detect patients with early-stage pancreatic cancer in urine specimens. Clin Cancer Res; 21(15); 3512–21. ©2015 AACR.

Objectives: Reducing cancer screening inequalities in England is a major focus of the 2011 Department of Health cancer outcome strategy. Screening coverage requires regular monitoring in order to implement targeted interventions where coverage is low. This study aimed to characterise districts with atypical coverage levels for cervical or breast screening. Design: Observational study of district-level coverage in the English Cervical and Breast screening programmes in 2012. Setting: England, UK. Participants: All English women invited to participate in the cervical (age group 25-49 and 50-64) and breast (age group 50-64) screening programmes. Outcomes: Risk adjustment models for coverage were developed based on district-level characteristics. Funnel plots of adjusted coverage were constructed, and atypical districts examined by correlation analysis. Results: Variability in coverage was primarily explained by population factors, whereas general practice characteristics had little independent effect. Deprivation and ethnicity other than white, Asian, black or mixed were independently associated with poorer coverage in both screening programmes, with ethnicity having the strongest effect; by comparison, the influence of Asian, black or mixed ethnic minority was limited. Deprivation, ethnicity and urbanisation largely accounted for the lower cervical screening coverage in London. However, for breast screening, being located in London remained a strong negative predictor. A subset of districts was identified as having atypical coverage across programmes. Correlates of deprivation in districts with relatively low adjusted coverage were substantially different from overall correlates of deprivation. Discussion: These results inform the continuing drive to reduce avoidable cancer deaths in England, and encourage implementation of targeted interventions in communities residing in districts identified as having atypically low coverage. Sequential implementation to monitor the impact of local interventions would help accrue evidence on 'what works'.