When is it considered reasonable to start a risky and uncomfortable treatment in critically ill patients? A random sample online questionnaire study.

BACKGROUND: Health care professionals have to judge the appropriateness of treatment in critical care on a daily basis. There is general consensus that critical care interventions should not be performed when they are inappropriate. It is not yet clear which chances of survival are considered necessary or which risk for serious disabilities is acceptable in quantitative terms for different stakeholders to start intensive care treatment. METHODS: We performed an anonymous online survey in a random sample of 1,052 participants recruited via email invitation and social media. Age, sex, nationality, education, professional involvement in health care, critical care medicine and treatment decisions in critical care medicine as well as personal experience with critical illness were assessed as potential influencing variables. Participants provided their opinion on the necessary chances of survival and the acceptable risk for serious disabilities to start a high-risk or uncomfortable therapy for themselves, relatives or for their patients on a scale of 0-100%. RESULTS: Answers ranged from 0 to 100% for all questions. A three-peak pattern with different distributions of the peaks was observed. Sex, education, being a health care professional, being involved in treatment decisions and religiosity influence these opinions. Male respondents and those with a university education would agree that a risky and uncomfortable treatment should be started even with a low chance of survival for themselves, relatives and patients. More respondents would choose a lower necessary chance of survival (0-33% survival) when deciding for patients compared to themselves or relatives to start a risky and uncomfortable treatment. On the other hand, the majority of respondents would accept only a low risk of severe disability for both themselves and their patients. CONCLUSION: No cut-off can be identified for the necessary chances of survival or the acceptable risk of disability to help quantify the "inappropriateness" of critical care treatment. Sex and education are the strongest influencing factors on this opinion. The large variation in personal opinions, depending on demographic and personality variables and education needs to be considered in the communication between health care professionals and patients or surrogates.

Correction to: Yttrium-90 radioembolization as a possible new treatment for brain cancer: proof of concept and safety analysis in a canine model.

An amendment to this paper has been published and can be accessed via the original article.

Yttrium-90 radioembolization as a possible new treatment for brain cancer: proof of concept and safety analysis in a canine model.

PURPOSE: To evaluate the safety, feasibility, and preliminary efficacy of yttrium-90 (90Y) radioembolization (RE) as a minimally invasive treatment in a canine model with presumed spontaneous brain cancers. MATERIALS: Three healthy research dogs (R1-R3) and five patient dogs with spontaneous intra-axial brain masses (P1-P5) underwent cerebral artery RE with 90Y glass microspheres (TheraSphere). 90Y-RE was performed on research dogs from the unilateral internal carotid artery (ICA), middle cerebral artery (MCA), and posterior cerebral artery (PCA) while animals with brain masses were treated from the ICA. Post-treatment 90Y PET/CT was performed along with serial neurological exams by a veterinary neurologist. One month after treatment, research dogs were euthanized and the brains were extracted and sent for microdosimetric and histopathologic analyses. Patient dogs received post-treatment MRI at 1-, 3-, and 6-month intervals with long-term veterinary follow-up. RESULTS: The average absorbed dose to treated tissue in R1-R3 was 14.0, 30.9, and 73.2 Gy, respectively, with maximum doses exceeding 1000 Gy. One month after treatment, research dog pathologic analysis revealed no evidence of cortical atrophy and rare foci consistent with chronic infarcts, e.g., < 2-mm diameter. Absorbed doses to masses in P1-P5 were 45.5, 57.6, 58.1, 45.4, and 64.1 Gy while the dose to uninvolved brain tissue was 15.4, 27.6, 19.2, 16.7, and 33.3 G, respectively. Among both research and patient animals, 6 developed acute neurologic deficits following treatment. However, in all surviving dogs, the deficits were transient resolving between 7 and 33 days post-therapy. At 1 month post-therapy, patient animals showed a 24-94% reduction in mass volume with partial response in P1, P3, and P4 at 6 months post-treatment. While P2 initially showed a response, by 5 months, the mass had advanced beyond pre-treatment size, and the dog was euthanized. CONCLUSION: This proof of concept demonstrates the technical feasibility and safety of 90Y-RE in dogs, while preliminary, initial data on the efficacy of 90Y-RE as a potential treatment for brain cancer is encouraging.

SIV Latency in Macrophages in the CNS.

Lentiviruses infect myeloid cells, leading to acute infection followed by persistent/latent infections not cleared by the host immune system. HIV and SIV are lentiviruses that infect CD4+ lymphocytes in addition to myeloid cells in blood and tissues. HIV infection of myeloid cells in brain, lung, and heart causes tissue-specific diseases that are mostly observed during severe immunosuppression, when the number of circulating CD4+ T cells declines to exceeding low levels. Antiretroviral therapy (ART) controls viral replication but does not successfully eliminate latent virus, which leads to viral rebound once ART is interrupted. HIV latency in CD4+ lymphocytes is the main focus of research and concern when HIV eradication efforts are considered. However, myeloid cells in tissues are long-lived and have not been routinely examined as a potential reservoir. Based on a quantitative viral outgrowth assay (QVOA) designed to evaluate latently infected CD4+ lymphocytes, a similar protocol was developed for the assessment of latently infected myeloid cells in blood and tissues. Using an SIV ART model, it was demonstrated that myeloid cells in blood and brain harbor latent SIV that can be reactivated and produce infectious virus in vitro, demonstrating that myeloid cells have the potential to be an additional latent reservoir of HIV that should be considered during HIV eradication strategies.

Cerebellar volume and cerebellocerebral structural covariance in schizophrenia: a multisite mega-analysis of 983 patients and 1349 healthy controls.

Although cerebellar involvement across a wide range of cognitive and neuropsychiatric phenotypes is increasingly being recognized, previous large-scale studies in schizophrenia (SZ) have primarily focused on supratentorial structures. Hence, the across-sample reproducibility, regional distribution, associations with cerebrocortical morphology and effect sizes of cerebellar relative to cerebral morphological differences in SZ are unknown. We addressed these questions in 983 patients with SZ spectrum disorders and 1349 healthy controls (HCs) from 14 international samples, using state-of-the-art image analysis pipelines optimized for both the cerebellum and the cerebrum. Results showed that total cerebellar grey matter volume was robustly reduced in SZ relative to HCs (Cohens's d=-0.35), with the strongest effects in cerebellar regions showing functional connectivity with frontoparietal cortices (d=-0.40). Effect sizes for cerebellar volumes were similar to the most consistently reported cerebral structural changes in SZ (e.g., hippocampus volume and frontotemporal cortical thickness), and were highly consistent across samples. Within groups, we further observed positive correlations between cerebellar volume and cerebral cortical thickness in frontotemporal regions (i.e., overlapping with areas that also showed reductions in SZ). This cerebellocerebral structural covariance was strongest in SZ, suggesting common underlying disease processes jointly affecting the cerebellum and the cerebrum. Finally, cerebellar volume reduction in SZ was highly consistent across the included age span (16-66 years) and present already in the youngest patients, a finding that is more consistent with neurodevelopmental than neurodegenerative etiology. Taken together, these novel findings establish the cerebellum as a key node in the distributed brain networks underlying SZ.

An SIV/macaque model targeted to study HIV-associated neurocognitive disorders.

Simian immunodeficiency virus (SIV) infection of pigtailed macaques is a highly representative and well-characterized animal model for HIV neuropathogenesis studies that provides an excellent opportunity to study and develop prognostic markers of HIV-associated neurocognitive disorders (HAND) for HIV-infected individuals. SIV studies can be performed in a controlled setting that enhances reproducibility and offers high-translational value. Similar to observations in HIV-infected patients receiving antiretroviral therapy (ART), ongoing neurodegeneration and inflammation are present in SIV-infected pigtailed macaques treated with suppressive ART. By developing quantitative viral outgrowth assays that measure both CD4+ T cells and macrophages harboring replication competent SIV as well as a highly sensitive mouse-based viral outgrowth assay, we have positioned the SIV/pigtailed macaque model to advance our understanding of latent cellular reservoirs, including potential CNS reservoirs, to promote HIV cure. In addition to contributing to our understanding of the pathogenesis of HAND, the SIV/pigtailed macaque model also provides an excellent opportunity to test innovative approaches to eliminate the latent HIV reservoir in the brain.

Brain Macrophages in Simian Immunodeficiency Virus-Infected, Antiretroviral-Suppressed Macaques: a Functional Latent Reservoir.

A human immunodeficiency virus (HIV) infection cure requires an understanding of the cellular and anatomical sites harboring virus that contribute to viral rebound upon treatment interruption. Despite antiretroviral therapy (ART), HIV-associated neurocognitive disorders (HAND) are reported in HIV-infected individuals on ART. Biomarkers for macrophage activation and neuronal damage in cerebrospinal fluid (CSF) of HIV-infected individuals demonstrate continued effects of HIV in brain and suggest that the central nervous system (CNS) may serve as a viral reservoir. Using a simian immunodeficiency virus (SIV)/macaque model for HIV encephalitis and AIDS, we evaluated whether infected cells persist in brain despite ART. Eight SIV-infected pig-tailed macaques were virally suppressed with ART, and plasma and CSF viremia levels were analyzed longitudinally. To assess whether virus persisted in brain macrophages (BrMΦ) in these macaques, we used a macrophage quantitative viral outgrowth assay (MΦ-QVOA), PCR, and in situ hybridization (ISH) to measure the frequency of infected cells and the levels of viral RNA and DNA in brain. Viral RNA in brain tissue of suppressed macaques was undetectable, although viral DNA was detected in all animals. The MΦ-QVOA demonstrated that the majority of suppressed animals contained latently infected BrMΦ. We also showed that virus produced in the MΦ-QVOAs was replication competent, suggesting that latently infected BrMΦ are capable of reestablishing productive infection upon treatment interruption. This report provides the first confirmation of the presence of replication-competent SIV in BrMΦ of ART-suppressed macaques and suggests that the highly debated issue of viral latency in macrophages, at least in brain, has been addressed in SIV-infected macaques treated with ART.IMPORTANCE Resting CD4+ T cells are currently the only cells that fit the definition of a latent reservoir. However, recent evidence suggests that HIV/SIV-infected macrophages persist despite ART. Markers of macrophage activation and neuronal damage are observed in the CSF of HIV-infected individuals and of SIV-infected macaques on suppressive ART regimens, suggesting that the CNS has continued virus infection and latent infection. A controversy exists as to whether brain macrophages represent a latent source of replication-competent virus capable of reestablishing infection upon treatment interruption. In this study, we demonstrated the presence of the latent macrophage reservoir in brains of SIV-infected ART-treated macaques and analyzed the reservoir using our established outgrowth assay to quantitate macrophages harboring replication-competent SIV genomes. Our results support the idea of the existence of other latent reservoirs in addition to resting CD4+ T cells and underscore the importance of macrophages in developing strategies to eradicate HIV.

Marked Enteropathy in an Accelerated Macaque Model of AIDS.

Enteropathy in HIV infection is not eliminated with combination antiretroviral therapy and is possibly linked to microbial translocation. We used a rapidly progressing SIV/pigtailed macaque model of HIV to examine enteropathy and microbial translocation. Histologic evidence of intestinal disease was observed in only half of infected macaques during late-stage infection (LSI). Combination antiretroviral therapy initiated during acute infection prevented intestinal disease. In the ileum and colon, enteropathy was associated with increased caspase-3 staining, decreased CD3+ T cells, and increased SIV-infected cells. CD3+ T cells were preserved in LSI animals without intestinal disease, and levels of CD3 staining in all LSI animals strongly correlated with the number of infected cells in the intestine and plasma viral load. Unexpectedly, there was little evidence of microbial translocation as measured by soluble CD14, soluble CD163, lipopolysaccharide binding protein, and microbial 16s ribosomal DNA. Loss of epithelial integrity indicated by loss of the tight junction protein claudin-3 was not observed during acute infection despite significantly fewer T cells. Claudin-3 was reduced in LSI animals with severe intestinal disease but did not correlate with increased microbial translocation. LSI animals that did not develop intestinal disease had increased T-cell intracytoplasmic antigen 1-positive cytotoxic T lymphocytes, suggesting a robust adaptive cytotoxic T-lymphocyte response may, in part, confer resilience to SIV-induced intestinal damage.

HIV Protease Inhibitors Alter Amyloid Precursor Protein Processing via ß-Site Amyloid Precursor Protein Cleaving Enzyme-1 Translational Up-Regulation.

Mounting evidence implicates antiretroviral (ARV) drugs as potential contributors to the persistence and evolution of clinical and pathological presentation of HIV-associated neurocognitive disorders in the post-ARV era. Based on their ability to induce endoplasmic reticulum (ER) stress in various cell types, we hypothesized that ARV-mediated ER stress in the central nervous system resulted in chronic dysregulation of the unfolded protein response and altered amyloid precursor protein (APP) processing. We used in vitro and in vivo models to show that HIV protease inhibitor (PI) class ARVs induced neuronal damage and ER stress, leading to PKR-like ER kinase-dependent phosphorylation of the eukaryotic translation initiation factor 2α and enhanced translation of ß-site APP cleaving enzyme-1 (BACE1). In addition, PIs induced ß-amyloid production, indicative of increased BACE1-mediated APP processing, in rodent neuroglial cultures and human APP-expressing Chinese hamster ovary cells. Inhibition of BACE1 activity protected against neuronal damage. Finally, ARVs administered to mice and SIV-infected macaques resulted in neuronal damage and BACE1 up-regulation in the central nervous system. These findings implicate a subset of PIs as potential mediators of neurodegeneration in HIV-associated neurocognitive disorders.

Splenic Damage during SIV Infection: Role of T-Cell Depletion and Macrophage Polarization and Infection.

The effects of HIV infection on spleen and its cellular subsets have not been fully characterized, particularly for macrophages in which diverse populations exist. We used an accelerated SIV-infected macaque model to examine longitudinal effects on T-cell and macrophage populations and their susceptibilities to infection. Substantial lymphoid depletion occurred, characterized by follicular burn out and a loss of CD3 T lymphocytes, which was associated with cellular activation and transient dysregulations in CD4/CD8 ratios and memory effector populations. In contrast, the loss of CD68 and CD163(+)CD68(+) macrophages and increase in CD163 cells was irreversible, which began during acute infection and persisted until terminal disease. Mac387 macrophages and monocytes were transiently recruited into spleen, but were not sufficient to mitigate the changes in macrophage subsets. Type I interferon, M2 polarizing genes, and chemokine-chemokine receptor signaling were up-regulated in spleen and drove macrophage alterations. SIV-infected T cells were numerous within the white pulp during acute infection, but were rarely observed thereafter. CD68, CD163, and Mac387 macrophages were highly infected, which primarily occurred in the red pulp independent of T cells. Few macrophages underwent apoptosis, indicating that they are a long-lasting target for HIV/SIV. Our results identify macrophages as an important contributor to HIV/SIV infection in spleen and in promoting morphologic changes through the loss of specific macrophage subsets that mediate splenic organization.

Quantitation of Productively Infected Monocytes and Macrophages of Simian Immunodeficiency Virus-Infected Macaques.

UNLABELLED: Despite the success of combined antiretroviral therapy (ART), human immunodeficiency virus (HIV) infection remains a lifelong infection because of latent viral reservoirs in infected patients. The contribution of CD4(+) T cells to infection and disease progression has been extensively studied. However, during early HIV infection, macrophages in brain and other tissues are infected and contribute to tissue-specific diseases, such as encephalitis and dementia in brain and pneumonia in lung. The extent of infection of monocytes and macrophages has not been rigorously assessed with assays comparable to those used to study infection of CD4(+) T cells and to evaluate the number of CD4(+) T cells that harbor infectious viral genomes. To assess the contribution of productively infected monocytes and macrophages to HIV- and simian immunodeficiency virus (SIV)-infected cells in vivo, we developed a quantitative virus outgrowth assay (QVOA) based on similar assays used to quantitate CD4(+) T cell latent reservoirs in HIV- and SIV-infected individuals in whom the infection is suppressed by ART. Myeloid cells expressing CD11b were serially diluted and cocultured with susceptible cells to amplify virus. T cell receptor ß RNA was measured as a control to assess the potential contribution of CD4(+) T cells in the assay. Virus production in the supernatant was quantitated by quantitative reverse transcription-PCR. Productively infected myeloid cells were detected in blood, bronchoalveolar lavage fluid, lungs, spleen, and brain, demonstrating that these cells persist throughout SIV infection and have the potential to contribute to the viral reservoir during ART. IMPORTANCE: Infection of CD4(+) T cells and their role as latent reservoirs have been rigorously assessed; however, the frequency of productively infected monocytes and macrophages in vivo has not been similarly studied. Myeloid cells, unlike lymphocytes, are resistant to the cytopathic effects of HIV. Moreover, tissue-resident macrophages have the ability to self-renew and persist in the body for months to years. Thus, tissue macrophages, once infected, have the characteristics of a potentially stable viral reservoir. A better understanding of the number of productively infected macrophages is crucial to further evaluate the role of infected myeloid cells as a potential viral reservoir. In the study described here we compared the frequency of productively infected CD4(+) T cells and macrophages in an SIV-infected macaque model. We developed a critical assay that will allow us to quantitate myeloid cells containing viral genomes that lead to productive infection in SIV-infected macaques and assess the role of macrophages as potential reservoirs.

Evaluation of the 'Jumping to conclusions' bias in different subgroups of the at-risk mental state: from cognitive basic symptoms to UHR criteria.

BACKGROUND: Patients with psychosis display the so-called 'Jumping to Conclusions' bias (JTC) - a tendency for hasty decision-making in probabilistic reasoning tasks. So far, only a few studies have evaluated the JTC bias in 'at-risk mental state' (ARMS) patients, specifically in ARMS samples fulfilling 'ultra-high risk' (UHR) criteria, thus not allowing for comparisons between different ARMS subgroups. METHOD: In the framework of the PREVENT (secondary prevention of schizophrenia) study, a JTC task was applied to 188 patients either fulfilling UHR criteria or presenting with cognitive basic symptoms (BS). Similar data were available for 30 healthy control participants matched for age, gender, education and premorbid verbal intelligence. ARMS patients were identified by the Structured Interview for Prodromal Symptoms (SIPS) and the Schizophrenia Proneness Instrument - Adult Version (SPI-A). RESULTS: The mean number of draws to decision (DTD) significantly differed between ARM -subgroups: UHR patients made significantly less draws to make a decision than ARMS patients with only cognitive BS. Furthermore, UHR patients tended to fulfil behavioural criteria for JTC more often than BS patients. In a secondary analysis, ARMS patients were much hastier in their decision-making than controls. In patients, DTD was moderately associated with positive and negative symptoms as well as disorganization and excitement. CONCLUSIONS: Our data indicate an enhanced JTC bias in the UHR group compared to ARMS patients with only cognitive BS. This underscores the importance of reasoning deficits within cognitive theories of the developing psychosis. Interactions with the liability to psychotic transitions and therapeutic interventions should be unravelled in longitudinal studies.

Longitudinal association between cognitive performance and obsessive-compulsive symptoms in patients with psychosis and unaffected siblings.

OBJECTIVE: Obsessive-compulsive symptoms (OCS) frequently occur in psychotic disorders. Cross-sectional associations between OCS and cognitive impairment have led to different causal explanations. Whereas one assumes that higher cognitive impairment reflects a risk factor for psychotic patients to develop OCS, another suggests that deficits reflect a consequence of OCS. This study investigated the longitudinal interrelation between OCS and cognitive functioning. METHOD: Baseline and follow-up data from 622 patients and 670 un-affected siblings from the 'Genetic Risk and Outcome in Psychosis' study were analyzed. Participants were allocated to groups according to the presence or absence of OCS at assessments and compared on several cognitive domains. RESULTS: Cross-sectional comparisons revealed no group differences in cognitive performance. Longitudinal analyses comparing the groups with changes in OCS revealed one significant group effect with more problems in set-shifting abilities in patient who reported OCS development at follow-up. Significant time and interaction effects were mainly due to improvement in immediate verbal recall and digit-symbol coding in patients and siblings who reported remission of OCS. CONCLUSION: Although insight into causality needs further exploration, our results do not confirm the hypothesis of pre-existing cognitive risk constellations. Findings suggest that remission of comorbid OCS results in improved immediate verbal recall and processing speed.

Distinct Patterns of Tryptophan Maintenance in Tissues during Kynurenine Pathway Activation in Simian Immunodeficiency Virus-Infected Macaques.

Induction of the kynurenine pathway (KP) of tryptophan (TRP) catabolism has been proposed to contribute to T cell dysfunction during human/simian immunodeficiency virus (SIV) infection via depletion of local TRP levels and production of immunomodulatory KP metabolites. However, while changes in TRP and KP metabolites have been observed in plasma, their levels in lymphoid tissues and levels of enzymes downstream of indoleamine 2,3-dioxygenase (IDO1) have been relatively unexplored. We used our SIV-infected pigtailed macaque model to analyze longitudinal changes in KP metabolites and enzymes by gas chromatography/mass spectrometry and NanoString nCounter gene expression analysis, respectively, in spleen and blood compared to changes previously established in brain and CSF. We found that TRP levels were remarkably stable in tissue sites despite robust depletion in the circulating plasma and CSF. We also demonstrated that intracellular TRP reserves were maintained in cultured cells even in the presence of depleted extracellular TRP levels. Kynurenine (KYN), 3-hydroxykynurenine, quinolinic acid, and the KP enzymes all displayed highly divergent patterns in the sites examined, though IDO1 expression always correlated with local KYN/TRP ratios. Finally, we demonstrated by fluorescence-activated cell sorting that myeloid dendritic cells and cells of monocytic lineage were the highest producers of IDO1 in chronically infected spleens. Overall, our study reveals insights into the tissue-specific regulation of KP enzymes and metabolites and, in particular, highlights the multiple mechanisms by which cells and tissues seek to prevent TRP starvation during inflammation.

EXPERIMENTAL CHALLENGE STUDY OF FV3-LIKE RANAVIRUS INFECTION IN PREVIOUSLY FV3-LIKE RANAVIRUS INFECTED EASTERN BOX TURTLES (TERRAPENE CAROLINA CAROLINA) TO ASSESS INFECTION AND SURVIVAL.

The Maryland Zoo in Baltimore experienced an outbreak of Frog virus-3 (FV3)-like ranavirus during the summer of 2011, during which 14 of 27 (52%) of its captive eastern box turtles (Terrapene carolina carolina) survived. To assess survival, immunity, and viral shedding, an experimental challenge study was performed in which the surviving, previously infected turtles were reinfected with the outbreak strain of FV3-like ranavirus. Seven turtles were inoculated with virus intramuscularly and four control turtles received saline intramuscularly. The turtles were monitored for 8 wk with blood and oral swabs collected for quantitative polymerase chain reaction (qPCR). During that time, one of seven (14%) inoculated turtles and none of the controls (0%) died; there was no significant difference in survival. Clinical signs of the inoculated turtles, except for the turtle that died, were mild compared to the original outbreak. Quantitative PCR for FV3-like ranavirus on blood and oral swabs was positive for all inoculated turtles and negative for all controls. The turtle that died had intracytoplasmic inclusion bodies in multiple organs. Three inoculated and two control turtles were euthanized at the end of the study. No inclusion bodies were present in any of the organs. Quantitative PCR detected FV3-like ranavirus in the spleen of a control turtle, which suggested persistence of the virus. The surviving five turtles were qPCR-negative for FV3-like ranavirus from blood and oral swabs after brumation. Quantitative PCR for Terrapene herpesvirus 1 found no association between ranavirus infection and herpesvirus loads. In conclusion, previously infected eastern box turtles can be reinfected with the same strain of FV3-like ranavirus and show mild to no clinical signs but can shed the virus from the oral cavity.

Quantitative Comparison of the Walk and Trot of Border Collies and Labrador Retrievers, Breeds with Different Performance Requirements.

INTRODUCTION: We hypothesized that breed differences of Border Collies and Labrador Retrievers would be reflected in the temporospatial characteristics of the walk and trot. MATERIALS AND METHODS: Twenty healthy Border Collies and 20 healthy Labrador Retrievers made three passes across a pressure sensing walkway system that recorded quantitative temporospatial information at a walk and a trot. The following variables were measured for each dog: velocity, total pressure index percentage (TPI%), ratio of weight borne on the thoracic vs. pelvic limbs (T/P TPI%), stance time percentage (ST%), and thoracic limb stride length (TSrL). RESULTS: The mean T/P TPI% for Border Collies at a walk and at a trot were significantly lower than for Labrador Retrievers (p = 0.0007 and p = 0.0003). Border Collies had a significantly lower ST% than Labrador Retrievers for the thoracic limbs and pelvic limbs at a walk (p = 0.0058 and 0.0003) and the trot (p = 0.0280 and 0.0448). There was no relationship between ST% and TSrL in Border Collies and an inverse correlation between ST% and TSrL in Labrador Retrievers (p = 0.0002). DISCUSSION: Key quantitative gait differences were identified in Border Collies and Labrador Retrievers, which could potentially provide each breed with an advantage for their working function.

Investigation of metamemory functioning in the at-risk mental state for psychosis.

BACKGROUND: Metamemory describes the monitoring and knowledge about one's memory capabilities. Patients with schizophrenia have been found to be less able in differentiating between correct and false answers (smaller confidence gap) when asked to provide retrospective confidence ratings in previous studies. Furthermore, higher proportions of very-high-confident but false responses have been found in this patient group (high knowledge corruption). Whether and how these biases contribute to the early pathogenesis of psychosis is yet unclear. This study thus aimed at investigating metamemory function in the early course of psychosis. METHOD: Patients in an at-risk mental state for psychosis (ARMS, n = 34), patients with a first episode of psychosis (FEP, n = 21) and healthy controls (HCs, n = 38) were compared on a verbal recognition task combined with retrospective confidence-level ratings. RESULTS: FEP patients showed the smallest confidence gap, followed by ARMS patients, followed by HCs. All groups differed significantly from each other. Regarding knowledge corruption, FEP patients differed significantly from HCs, whereas a statistical trend was revealed in comparison of ARMS and FEP groups. Correlations were revealed between metamemory, measures of positive symptoms and working memory performance. CONCLUSIONS: These data underline the presence of a metamemory bias in ARMS patients which is even more pronounced in FEP patients. The bias might represent an early cognitive marker of the beginning psychotic state. Longitudinal studies are needed to unravel whether metacognitive deficits predict the transition to psychosis and to evaluate therapeutic interventions.

Contractile cell forces deform macroscopic cantilevers and quantify biomaterial performance.

Cells require adhesion to survive, proliferate and migrate, as well as for wound healing and many other functions. The strength of contractile cell forces on an underlying surface is a highly relevant quantity to measure the affinity of cells to a rigid surface with and without coating. Here we show with experimental and theoretical studies that these forces create surface stresses that are sufficient to induce measurable bending of macroscopic cantilevers. Since contractile forces are linked to the formation of focal contacts, results give information on adhesion promoting qualities and allow a comparison of very diverse materials. In exemplary studies, in vitro fibroblast adhesion on the magnetic shape memory alloy Fe-Pd and on the l-lysine derived plasma-functionalized polymer PPLL was determined. We show that cells on Fe-Pd are able to induce surface stresses three times as high as on pure titanium cantilevers. A further increase was observed for PPLL, where the contractile forces are four times higher than on the titanium reference. In addition, we performed finite element simulations on the beam bending to back up the calculation of contractile forces from cantilever bending under non-homogenous surface stress. Our findings consolidate the role of contractile forces as a meaningful measure of biomaterial performance.

Neurocognitive dysfunction and pharmacological intervention using guanfacine in a rhesus macaque model of self-injurious behavior.

Self-injurious behavior (SIB) is a common comorbidity of psychiatric disorders but there is a dearth of information about neurological mechanisms underlying the behavior, and few animal models exist. SIB in humans is characterized by any intentional self-directed behavior that leads to wounds, whereas in macaques it is not always accompanied by wounds. We describe a cohort of rhesus macaques displaying SIB as adults, in which changes within the central nervous system were associated with the SIB. In these macaques, increases in central nervous system striatal dopamine (DA) receptor binding (BPND) measured by positron emission tomography (PET) [11C]raclopride imaging correlated with severity of wounding (rs=0.662, P=0.014). Furthermore, utilizing standardized cognitive function tests, we showed that impulsivity (stop signal reaction time, SSRT) and deficits in attentional set shifting (intra-/extradimensional shift) were correlated with increased severity of SIB (rs=0.563, P=0.045 and rs=0.692, P=0.009, respectively). We also tested the efficacy of guanfacine, an α2A adrenergic agonist that acts to improve postsynaptic transmission of neuronal impulses, in reducing SIB. A subset of these animals were enrolled in a randomized experimenter-blinded study that demonstrated guanfacine decreased the severity of wounding in treated animals compared with vehicle-only-treated controls (P=0.043), with residual beneficial effects seen for several weeks after cessation of therapy. Animals with the highest severity of SIB that received guanfacine also showed the most significant improvement (rs=-0.761, P=0.009). The elevated PET BPND was likely due to low intrasynaptic DA, which in turn may have been improved by guanfacine. With underlying physiology potentially representative of the human condition and the ability to affect outcome measures of disease using pharmacotherapy, this model represents a unique opportunity to further our understanding of the biology and treatment of SIB in both animals and humans.

A Murine Viral Outgrowth Assay to Detect Residual HIV Type 1 in Patients With Undetectable Viral Loads.

BACKGROUND: Sensitive assays are needed for detection of residual human immunodeficiency virus (HIV) in patients with undetectable plasma viral loads to determine whether eradication strategies are effective. The gold standard quantitative viral outgrowth assay (QVOA) underestimates the magnitude of the viral reservoir. We sought to determine whether xenograft of leukocytes from HIV type 1 (HIV)-infected patients with undetectable plasma viral loads into immunocompromised mice would result in viral amplification. METHODS: Peripheral blood mononuclear cells or purified CD4(+) T cells from HIV or simian immunodeficiency virus (SIV)-infected subjects with undetectable plasma viral loads were adoptively transferred into NOD.Cg-Prkdc(scid)Il2rg(tm1Wjl)/SzJ (NSG) mice. The mice were monitored for viremia following depletion of human CD8(+) T cells to minimize antiviral activity. In some cases, humanized mice were also treated with activating anti-CD3 antibody. RESULTS: With this murine viral outgrowth assay (MVOA), we successfully amplified replication-competent HIV or SIV from all subjects tested, including 5 HIV-positive patients receiving suppressive antiretroviral therapy (ART) and 6 elite controllers or suppressors who were maintaining undetectable viral loads without ART, including an elite suppressor from whom we were unable to recover virus by QVOA. CONCLUSIONS: Our results suggest that the MVOA has the potential to serve as a powerful tool to identify residual HIV in patients with undetectable viral loads.