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Herbal-induced liver injury (HILI) is an important and increasingly concerning cause of liver toxicity, and this study presents recent updates to the literature. An extensive literature review was conducted encompassing September 2019 through March 2021. Studies with clinically significant findings were analyzed and included in this review. We emphasized those studies that provided a causality assessment methodology, such as Roussel Uclaf Causality Assessment Method scores. Our review includes reports of individual herbals, including Garcinia cambogia, green tea extract, kratom as well as classes such as performance enhancing supplements, Traditional Chinese medicine, Ayurvedic medicine and herbal contamination. Newly described herbals include ashwagandha, boldo, skyfruit, and ‘Thermo gun’. Several studies discussing data from national registries, including the United States Drug-Induced Liver Injury (DILI) Network, Spanish DILI Registry, and Latin American DILI Network were incorporated. There has also been a continued interest in hepatoprotection, with promising use of herbals to counter hepatotoxicity from anti-tubercular medications. We also elucidated the current legal conversation surrounding use of herbals by presenting updates from the Federal Drug Administration. The highlights of the literature over the past year indicate interest in HILI that will continue as the supplement industry in the United States grows.

Drug-induced liver injury (DILI) remains an important, yet challenging diagnosis for physicians. Each year, additional drugs are implicated in DILI and this year was no different, with more than 1400 articles published on the subject. This review examines some of the most significant highlights and controversies in DILI-related research over the past year and their implications for clinical practice. Several new drugs were approved by the US Food and Drug Administration including a number of drugs implicated in causing DILI, particularly among the chemotherapeutic classes. The COVID-19 pandemic was also a major focus of attention in 2020 and we discuss some of the notable aspects of COVID-19-related liver injury and its implications for diagnosing DILI. Updates in diagnostic and causality assessments related to DILI such as the Roussel Uclaf Causality Assessment Method are included, mindful that there is still no single biomarker or diagnostic tool to unequivocally diagnose DILI. Glutamate dehydrogenase received renewed attention as being more specific than alanine aminotransferase. There were a few new reports of previously unrecognized hepatotoxins, including immune modulators and novel gene therapy drugs that we highlight. Updates and new developments of previously described hepatotoxins, such as immune checkpoint inhibitors and anti-tuberculosis drugs are reviewed. Finally, novel technologies such as organoid culture systems to better predict DILI preclinically may be coming of age and determinants of hepatocyte loss, such as calculating PALT are poised to improve our current means of estimating DILI severity and the risk of acute liver failure.

Inducible gene expression systems are valuable tools for studying biological processes. We previously developed an optogenetic gene expression system called TAEL that is optimized for use in zebrafish. When illuminated with blue light, TAEL transcription factors dimerize and activate gene expression downstream of the TAEL-responsive C120 promoter. By using light as the inducing agent, the TAEL/C120 system overcomes limitations of traditional inducible expression systems by enabling fine spatial and temporal regulation of gene expression. Here, we describe ongoing efforts to improve the TAEL/C120 system. We made modifications to both the TAEL transcriptional activator and the C120 regulatory element, collectively referred to as TAEL 2.0. We demonstrate that TAEL 2.0 consistently induces higher levels of reporter gene expression and at a faster rate, but with comparable background and toxicity as the original TAEL system. With these improvements, we were able to create functional stable transgenic lines to express the TAEL 2.0 transcription factor either ubiquitously or with a tissue-specific promoter. We demonstrate that the ubiquitous line in particular can be used to induce expression at late embryonic and larval stages, addressing a major deficiency of the original TAEL system. This improved optogenetic expression system will be a broadly useful resource for the zebrafish community.

Racial concordance between patients and clinician has been linked to improved satisfaction and patient outcomes. (1) To examine the likelihood of clinician-patient racial concordance in non-Hispanic White, non-Hispanic Black, Asian, and Hispanic patients and (2) to evaluate the impact of patient-clinician race concordance on healthcare use and expenditures within each racial ethnic group. We analyzed data from the 2010–2016 Medical Expenditure Panel Survey (MEPS). We used bivariate and multivariate models to assess the association between patient-clinician race concordance and emergency department (ED) use, hospitalizations, and total healthcare expenses, controlling for patient socio-demographic factors, insurance coverage, health status, and survey year fixed effects. Of the 50,626 adults in the analysis sample, 32,350 had racial concordance with their clinician. Among Asian and Hispanic patients, low income, less education, and non-private insurance were associated with an increased likelihood of patient-clinician racial concordance. Emergency department use was lower among Whites and Hispanics with concordant clinicians compared to those without a discordant clinician (15.6% vs. 17.3%, p = 0.02 and 12.9% vs. 16.2%, p = 0.01 respectively). Total healthcare expenditures were lower among Black, Asian, and Hispanic patients with race-concordant clinicians than those with discordant clinicians (14%, 34%, and 20%, p

Inducible gene expression systems are an invaluable tool for studying biological processes. Optogenetic expression systems can provide precise control over gene expression timing, location, and amplitude using light as the inducing agent. In this protocol, an optogenetic expression system is used to achieve light-inducible gene expression in zebrafish embryos. This system relies on an engineered transcription factor called TAEL based on a naturally occurring light-activated transcription factor from the bacterium E. litoralis. When illuminated with blue light, TAEL dimerizes, binds to its cognate regulatory element called C120, and activates transcription. This protocol uses transgenic zebrafish embryos that express the TAEL transcription factor under the control of the ubiquitous ubb promoter. At the same time, the C120 regulatory element drives the expression of a fluorescent reporter gene (GFP). Using a simple LED panel to deliver activating blue light, induction of GFP expression can first be detected after 30 min of illumination and reaches a peak of more than 130-fold induction after 3 h of light treatment. Expression induction can be assessed by quantitative real-time PCR (qRT-PCR) and by fluorescence microscopy. This method is a versatile and easy-to-use approach for optogenetic gene expression.

Purpose Cardiopulmonary resuscitation is common in the United States, with >200,000 people experiencing an in-hospital cardiac arrest (IHCA) annually. Recent medication shortages have raised the question of the frequency and type of medication used during cardiac arrest resuscitation. We sought to determine the frequency and quantity of medications used during IHCA. Methods This retrospective, single-center, medical record review was performed at a large, urban teaching hospital. Adults ≥18 years old who had an IHCA with confirmed loss of pulse between January 2017 and March 2018 were identified. A standardized data collection tool was used to extract data from the electronic medical record. The primary outcome was the frequency and quantity of medications used during the IHCA. Secondary outcomes included median time to defibrillation and frequency of sodium bicarbonate use, including among patients with end-stage renal disease (ESRD). Findings Criteria were met for 181 IHCA events. Demographic characteristics were 71% black, 17% white, mean age of 65 years, and 46% women. Epinephrine was given in 86.7% of the arrests, with a mean cumulative dose of 4.2 mg. Sodium bicarbonate was given in 63.5% of the arrests, with a mean cumulative dose of 9.0 g (1.9 amps). Amiodarone was given in 30.9% of the arrests, with a mean cumulative dose of 311.8 mg. Median time to defibrillation was 2 min (interquartile range, 1–4 min). Preexisting ESRD was present in 24.8% of patients, of whom 71.1% received sodium bicarbonate. Sodium bicarbonate administration was associated with a lower likelihood of survival to discharge (odds ratio [OR] = 0.27; 95% CI, 0.11–0.66) as well as a lower rate of return to spontaneous circulation (ROSC) (OR = 0.35; 95% CI, 0.13–0.95). Magnesium administration was associated with a lower rate of ROSC (OR = 0.39; 95% CI, 0.15–0.98). Of note, in patients with preexisting ESRD, no medications were significantly associated with a change in likelihood of survival to discharge or rate of ROSC. In patients without preexisting ESRD, magnesium was associated with a lower rate of ROSC (OR = 0.23; 95% CI, 0.08–0.77). Implications We found that in a hospital with established rapid response and code blue teams, numerous medications that are not recommended for routine use in cardiac arrest are still administered at significant frequencies. Furthermore, substantial amounts of drugs with known recent shortage are used in IHCA. Inc.

Study Objectives: Every year 33,000 people suffer an IHCA with an initial shockable rhythm in the US. Rapid Response Teams may increase time to defibrillation and are not associated with lower in-hospital mortality. We sought to describe characteristics of sudden IHCAs with a shockable initial rhythm in a system with mature Rapid Response and Code Blue teams, in particular, time to defibrillation. Methods: Retrospective chart review at a large, urban teaching hospital with mature Rapid Response and Code Blue teams. Adults in whom a “Code Blue” was called with confirmed cardiac arrest between Jan 2017 and Mar 2018 were included. Codes with incomplete data or that occurred in the ED or ICU were excluded. The “Code Blue” team consists of 1-3 Nurse Responders, a nursing supervisor, a respiratory therapist, Anesthesiology, a critical care resident, and a surgical resident. Each ward has a defibrillator and standardized code cart. Trained and supervised research assistants used a standardized data collection tool to extract demographic information, comorbidities and event related data from code sheets, history and physical, progress notes, discharge and death summaries. Events were categorized by initial rhythm as shockable or non-shockable. Time to defibrillation was defined as the interval from reported time of initial recognition of cardiac arrest to the reported time of first attempted defibrillation. Fisher’s exact testing was used to test for statistical significance. Results: A total of 183 “Code Blues” met criteria. Demographics: 71% black; mean age 65; and 46% women. Fifty-five (30%) survived to hospital discharge. Forty (21.3%) had an initial shockable rhythm of whom 21 (52.5%) survived to hospital discharge. Of the 40 patients that had an initial shockable rhythm, 36 were defibrillated. Median time to defibrillation was 2 minutes [IQR = 1-4]. Of those defibrillated within 2 minutes, survival was 64% vs 33% (P = 0.102) among those defibrillated in > 2 minutes. Of the 143 patients that had a nonshockable initial rhythm, 34 (23.8%) survived to hospital discharge. Conclusion: In a system with mature Rapid Response and Code Blue teams, time to defibrillation among IHCA patients with a shockable initial rhythm is 2 minutes.

Introduction: Resuscitation medication shortages are widespread across the US. We sought to determine the frequency and quantity of meds used during IHCA. Methods: Retrospective, single center, chart review at a large, urban teaching hospital. Adults over 18 who suffered IHCA between Jan 2017 and Mar 2018 were identified. Trained and supervised research assistants used a standardized data tool to extract data from the EMR. Primary outcome was the frequency and quantity of ACLS meds used during IHCA. Secondary outcomes included evaluating the association of med administration with ROSC and survival as well as the use of sodium bicarb with survival in patients with pre-existing end stage renal disease. Results: Criteria were met for 181 IHCA events. Demographics: 71% (128 of 181) black; mean age 65; and 46% (83 of 181) women. Epi was given in 86.7% (157 of 181) cases, with average cumulative dose of 4.2 mg, sodium bicarb given in 63.5% (115 of 181), average dose of 1.9 amps, calcium chloride given in 39.2% (71 of 181), average dose of 1.9 amps, amiodarone was given in 30.9% (56 of 181), average dose of 311.8 mg, and atropine was given in 13.8% (25 of 181), average dose of 1.3 amps. Administration of sodium bicarb was associated with lower rates of ROSC (OR 0.31, 95% CI 0.18 to 0.83) and lower survival (OR 0.31, 95% CI 0.13 to 0.73). Administration of mag sulfate was associated with lower rates of ROSC (OR 0.33, 95% CI 0.13 to 0.83), but no difference in survival (OR 0.34, 95% CI 0.10 to 1.14). Administration of epi, amiodarone, calcium, dextrose, or atropine was not associated with a change in rates of ROSC or survival. In patients with pre-existing ESRD (45 of 181), 73.3% (33 of 45) received sodium bicarb, with 51.5% (17 of 33) achieving ROSC, and 12.1% (4 of 33) surviving to discharge. In patients without ESRD (136 of 181), 60.3% (82 of 136) received sodium bicarb, with 65.9% (54/82) achieving ROSC, and 22.0% (18 of 82) surviving to discharge. (12.1% vs 22.0% p = 0.224). Conclusions: Substantial amounts of drugs with known recent shortage are used in IHCA with no significant increase in ROSC or survival to discharge. Administration of sodium bicarb during IHCA is associated with lower rates of ROSC and survival. These results may be due to confounders such as code duration.

During embryogenesis the germ layers, including the endoderm, undergo convergence and extension (C&E) movements to narrow and elongate the body plan. In zebrafish, the dorsal migration of endodermal cells during gastrulation is controlled by chemokine signaling, but little is known about how they migrate during segmentation. Here we show that Glypican4 (Gpc4), a member of the heparin sulphate proteoglycan family, is required for efficient migration of anterior endodermal cells during early segmentation, regulating Rac activation to maintain polarized actin-rich lamellipodia. An endoderm transplantation assay showed that Gpc4 regulates endoderm migration in a non-cell-autonomous fashion. Further analyses revealed that the impaired endoderm migration in gpc4 mutants results from increases in the expression and assembly of fibronectin and laminin, major components of the extracellular matrix (ECM). Notably, we found that the matrix metalloproteinase 14 (Mmp14a/b) are required for the control of ECM expression during endoderm migration, with Gpc4 acting through Mmp14a/b to limit ECM expression. Our results suggest that Gpc4 is critical for generating the environment required for efficient migration of endodermal cells, uncovering a novel function of Gpc4 during development.

During gastrulation, endodermal cells actively migrate to the interior of the embryo, but the signals that initiate and coordinate this migration are poorly understood. By transplanting ectopically-induced endodermal cells far from the normal location of endoderm specification, we identified the inputs that drive internalization without the confounding influences of fate specification and global morphogenic movements. We find that Nodal signaling triggers an autocrine circuit for initiating endodermal internalization. Activation of the Nodal receptor directs endodermal specification through sox32 and also induces expression of more Nodal ligands. These ligands act in an autocrine fashion to initiate endodermal cell sorting. Our work defines an “AND” gate consisting of sox32-dependent endodermal specification and Nodal ligand reception controlling endodermal cell sorting to the inner layer of the embryo at the onset of gastrulation.

© 2017. Published by The Company of Biologists Ltd. Here, we describe an optogenetic gene expression system optimized for use in zebrafish. This system overcomes the limitations of current inducible expression systems by enabling robust spatial and temporal regulation of gene expression in living organisms. Because existing optogenetic systems show toxicity in zebrafish, we re-engineered the blue-light-activated EL222 system for minimal toxicity while exhibiting a large range of induction, fine spatial precision and rapid kinetics. We validate several strategies to spatially restrict illumination and thus gene induction with our new TAEL (TA4-EL222) system. As a functional example, we show that TAEL is able to induce ectopic endodermal cells in the presumptive ectoderm via targeted sox32 induction. We also demonstrate that TAEL can be used to resolve multiple roles of Nodal signaling at different stages of embryonic development. Finally, we show how inducible gene editing can be achieved by combining the TAEL and CRISPR/Cas9 systems. This toolkit should be a broadly useful resource for the fish community.

Background As with many clinical services, the number of patients requiring clinical pharmacist care exceeds the supply of those trained to provide it, so leaders and clinicians must make choices about which services to provide. A ‘Quality Actions’ (QA) framework has been proposed that provides for clinician-driven, systematic, transparent quantitative characterisation of individual QAs in terms of their value. This forms a basis for enhancement of quality of care. Objective To evaluate whether the value score is a feasible means of characterising the relative value of QAs among inpatient general medical pharmacists in a large multi-center health region. Methods Prospective study. In phase I, a set of six commonly performed QAs were identified by practitioners. In phase II, respondents scored all the QA elements across the six study QAs. Value scores were computed, the QAs ranked, and agreement among raters was assessed using intraclass correlation coefficients (ICCs). Sensitivity analyses were conducted to assess robustness of the rankings. Key findings Six study QAs were identified in phase I, and 43 pharmacists (43%) participated in phase II. The value scores were generally distinguishable and robust to changes in weighting strategies. The ICC across all variables was 0.48 (95% CI 0.38–0.62), indicating good overall agreement. Vancomycin dosing showed excellent agreement, whereas streamlining of antimicrobial therapy and warfarin dosing in atrial fibrillation had the poorest agreement. Conclusions It is feasible to develop a rank-ordered set of quality actions using a clinician-driven value score system. Good agreement between clinicians can be achieved using this system, and it is capable of identifying areas of disagreement, which may foster dialogue and focus educational efforts. Using this system may assist clinical service prioritisation and quality of care enhancement efforts.

One barrier to widespread public access to empirically supported treatments (ESTs) is the limited availability and high cost of professionals trained to deliver them. Our earlier work from two clinical trials demonstrated that front-line addiction counselors could be trained to deliver a manualized, group-based cognitive behavioral therapy (GCBT) for depression, a prototypic example of an EST, with a high level of adherence and competence. This follow-up article provides specific recommendations for the selection and initial training of counselors, and for the structure and process of their ongoing clinical supervision. Unique challenges in working with counselors unaccustomed to traditional clinical supervision are highlighted. The recommendations are based on comprehensive feedback derived from clinician notes taken throughout the clinical trials, a focus group with counselors conducted one year following implementation, and interviews with key organization executives and administrators.

Objective Managing newly diagnosed pediatric type 1 diabetes mellitus is challenging for patients and their families. This study evaluates the usefulness and accessibility of a new provincial educational resource for pediatric type 1 diabetes, A Guide for Families: Diabetes Care for Children and Teens (the Guide). Methods Qualitative feedback about the Guide was elicited from 2 groups of users in British Columbia (BC): 1) parents and pediatric patients newly diagnosed with type 1 diabetes who received the Guide during their initial diabetes education; and 2) diabetes educators who disseminate the Guide. Educators completed telephone interviews or questionnaires. Parents or patients completed telephone interviews. Results Forty Guide users participated, including 20 parents/patients and 20 educators. Participants described the Guide as easy to use; they appreciated the appeal, plain language, content and perceived usefulness. Educators frequently accessed the resource on-line. Parents/patients described the Guide as a valuable resource during their initial experiences with diabetes. Educators valued the Guide as a standardized educational resource for pediatric type 1 diabetes in BC. Conclusions Our results show that the Guide is a successful educational resource, with potential to facilitate standardization of diabetes education across BC Health Regions for parents and patients newly diagnosed with pediatric type 1 diabetes. This study supports the use of plain language to enhance the appeal and usefulness of diabetes education materials; it adds to the existing body of research that supports improvements in the accessibility and usefulness of diabetes educational resources.

Adhesion controls growth cone motility, yet the effects of axon guidance cues on adhesion site dynamics are poorly understood. Here we show that ephrin-A1 reduces retinal ganglion cell (RGC) axon outgrowth by stabilizing existing adhesions and inhibiting new adhesion assembly. Ephrin-A1 activates focal adhesion kinase (FAK) in an integrin- and Src-dependent manner and the effects of ephrin-A1 on growth cone motility require FAK activation. We also find that FAK is expressed in a high temporal to low nasal gradient in RGCs, similar to EphA receptors, and that balanced FAK activation is necessary for optimal axon outgrowth. Last, we find that FAK is required for proper topographic positioning of retinal axons along the anterior–posterior axis of the optic tectum in bothXenopusand zebrafish, a guidance decision mediated in part by A-type ephrins. Together, our data suggest that ephrin-A1 controls growth cone advance by modulating adhesive point contacts through FAK activation and that graded FAK signaling is an important component of ephrin-A-mediated retinotopic mapping.

Introduction Evidence based psychotherapies (EBPs) remain underutilized. Models for EBP training and implementation that are cost-effective, minimally disruptive, and sufficiently flexible are needed. Internet-based technology is a promising platform, but questions remain about how this technology can address the barriers to implementation. We developed and examined the implementation of an online training for the Building Recovery by Improving Goals, Habits, and Thoughts (BRIGHT) intervention—a manualized, sixteen-session group depression treatment for individuals with substance use disorders (SUDs). We explored the feasibility of replacing in-person BRIGHT training with a self-paced, online training. Methods A highly partnered and iterative process was followed to translate the written BRIGHT manual and associated didactic training materials into a media rich, interactive, and detailed (12–16h) online training. Subsequently, 8 volunteer counselors across 7 Veterans' Affairs SUD programs completed the training. Semi-structured interviews focused on the counselors' experiences and their plans for implementing BRIGHT groups. A template approach, using a mixture of deductive and inductive coding, was used for data analyses. Findings The most important barrier to completing training was a lack of protected time. Most counselors were not afforded protected time and reported a sometimes frustrating and fragmented training experience. Many used personal time at work and at home to complete the work. Facilitators to completing the training included positive reactions/attitudes towards the training modules, supervisor support, counselor dedication, and strong beliefs supporting providing services for depression. Many counselors were also concerned about the feasibility of fitting 16 group sessions (2h each) into their program's clinical schedule, but many had devised potential solutions or "work-arounds" to accommodate or approximate the recommended treatment course (e.g., using lunch times, reducing some content/exercises). Conclusion This work contributes to the literature on implementation of complex EBPs and addresses the strengths and limitations of web-based technologies in supporting the implementation of EBPs.

Extracellular cues guide axon outgrowth by activating intracellular signaling cascades that control the growth cone cytoskeleton. However, the spatial and temporal coordination of signaling intermediates remains essentially unknown. Live imaging of tyrosine phosphorylation in growth cones revealed dynamic phospho-tyrosine (PY) signals in filopodia that directly correlate with filopodial behavior. Local PY signals are generated at distal tips of filopodia during extension and are lost during retraction. Active Src family kinases localize to the tips of filopodia, and Src activity regulates both filopodial dynamics and local PY signaling. Positive guidance cues stimulate filopodial motility by locally increasing tyrosine phosphorylation in a cell division cycle 42 (Cdc42)-dependent manner. Locally reduced Src activity on one side of the growth cone generates an asymmetry in filopodial motility and PY signaling that promotes repulsive turning, suggesting that local changes in filopodial PY levels may underlie growth cone pathfinding decisions. p21-activated kinase (PAK), a Cdc42 effector whose activity is regulated by Src phosphorylation, also localizes to the tips of extending filopodia and controls filopodial motility. Coordinated activation of cytoskeletal effector proteins by GTPase binding and Src-mediated tyrosine phosphorylation may function to produce specific growth cone behaviors in response to guidance cues.

Studies have reported that certain measures of intrafamilial transactions are associated with an increased risk both for the initial onset of schizophrenia and for its recurrence following the initial episode of disorder. Two of the most studied of these are communication deviance (CD), a measure of subclinical thought disorder expressed in speech, and expressed emotion (EE), defined as notable attitudes of criticism and/or emotional overinvolvement manifested in a semistructured interview. A previous study (Goldstein et al. 1992) examined whether these two measures were associated with the presence of a diagnosable psychiatric disorder in the biological parents of recent-onset schizophrenia patients. In general, they were not. The present study went one step further. It examined whether these same measures were correlated with family history of schizophrenia or affective disorder in the biological parents and siblings of these same parents. High EE was not associated with a greater family history of schizophrenia spectrum disorders among the parent's parents and siblings but was unexpectedly found to be inversely associated with familial affective disorders. In contrast, CD was associated with a family history of schizophrenia spectrum disorders among the parent's parents and siblings. The findings are consistent with the possibility that CD may be an indicator of a genetic vulnerability factor for schizophrenia.

Background: No prior study of morbid risk in relatives of schizophrenia probands has, to our knowledge, focused solely on those with a recent onset of illness. Given that studies starting with chronic schizophrenia probands may exclude some individuals who have a more benign illness course, the examination of morbid risks among first-degree relatives of recent-onset schizophrenia patients is of substantial interest.

Five Minute Speech Sample Expressed Emotion (FMSS-EE) was examined in families of youth with depressive disorders, nondepressed youth with attention deficit/hyperactivity disorder (ADHD), and community controls screened for the absence of depression and ADHD. Consistent with the hypothesis that FMSS-EE shows some specificity as a risk factor for depression, rates of critical EE were significantly higher among mothers of youth with depression as compared to mothers of nondepressed youth with ADHD, or mothers of controls. When both mothers' and fathers' scores were used to generate family EE ratings, rates of overall EE and critical EE were significantly higher for the depressed group than the control group, but the nondepressed ADHD group did not differ significantly from the other groups. Results support the hypothesis that critical EE in mothers shows some specificity as a risk factor or correlate of depression in youth.

BackgroundPrevious research has generally found that variations in relatives' affective attitudes (expressed emotion; EE) towards a schizophrenic family member could not be accounted for by differences in the severity or form of the patient's symptomatology. These findings have been based on clinicians' ratings of psychopathology in patients.MethodTo approach the question from a different perspective, videotaped interactions between a patient and family members, obtained four to five weeks after hospital discharge, were coded for subclinical signs of psychopathology expressed by the patient. The Behavioral Subclinical Rating Scale (BSRS) was developed to compare subclinical levels of non-verbal and paralinguistic symptoms expressed by patients from both high- and low-EE families.ResultsHighly significant differences were found in the BSRS data. Patients from high-EE families showed more hostile and unusual behaviour with relatives than those from low-EE homes, who, in contrast, showed more anxious behaviour.ConclusionThese data suggest that a complex transactional model is necessary to understand how family attitudes evolve during the course of a relatives' schizophrenic disorder.

Disproportionately greater deficits in semantic relative to phonemic verbal fluency are seen in Alzheimer's disease (AD) and have been attributed to neurodegenerative changes in the temporal lobe. Amnestic (AMN) mild cognitive impairment (MCI), which often represents incipient AD, is also characterized by early temporal lobe neuropathology, but previous comparisons of verbal fluency between AD and AMN MCI have yielded mixed results. We examined semantic and phonemic verbal fluency performance in 399 individuals (78 AD, 138 AMN MCI, 72 non-amnestic MCI, and 111 cognitively normal controls). Similar verbal fluency patterns were seen in AMN MCI and AD; both groups exhibited disproportionately poorer performance on semantic verbal fluency relative to normal controls. However, relative verbal fluency indices performed more poorly than individual semantic or phonemic verbal fluency indices for discriminating AMN MCI or AD participants from normal controls, suggesting that they are unlikely to provide additional utility for predicting progression from MCI to AD.

Nodal, acting through Prex1 and Rac1, promotes dynamic actin and random motility in endodermal cells during early gastrulation., Embryo morphogenesis is driven by dynamic cell behaviors, including migration, that are coordinated with fate specification and differentiation, but how such coordination is achieved remains poorly understood. During zebrafish gastrulation, endodermal cells sequentially exhibit first random, nonpersistent migration followed by oriented, persistent migration and finally collective migration. Using a novel transgenic line that labels the endodermal actin cytoskeleton, we found that these stage-dependent changes in migratory behavior correlated with changes in actin dynamics. The dynamic actin and random motility exhibited during early gastrulation were dependent on both Nodal and Rac1 signaling. We further identified the Rac-specific guanine nucleotide exchange factor Prex1 as a Nodal target and showed that it mediated Nodal-dependent random motility. Reducing Rac1 activity in endodermal cells caused them to bypass the random migration phase and aberrantly contribute to mesodermal tissues. Together, our results reveal a novel role for Nodal signaling in regulating actin dynamics and migration behavior, which are crucial for endodermal morphogenesis and cell fate decisions.

This paper describes efforts to explicate the significance of schizophrenic patients' sub-clinical psychopathology (SCP) to affective attitudes expressed by relatives about these patients. Using data from two 10-minute interactions between patients and close relatives (usually parents), verbal and non-verbal behaviors were scored for signs of SCP by the patient. Scores reflective of more overt signs of SCP were highly related to relatives' expressed emotion status and their affective style when interacting with the patient, suggesting that a complex transactional model best explains the connection between high EE status of a relative and the risk for patient relapse.

Members of the Slit family of secreted ligands interact with Roundabout (Robo) receptors to provide guidance cues for many cell types. For example, Slit/Robo signaling elicits repulsion of axons during neural development, whereas in endothelial cells this pathway inhibits or promotes angiogenesis depending on the cellular context. Here, we show that miR-218 is intronically encoded in slit2 and slit3 and that it suppresses Robo1 and Robo2 expression. Our data indicate that miR-218 and multiple Slit/Robo signaling components are required for heart tube formation in zebrafish and that this network modulates the previously unappreciated function of Vegf signaling in this process. These findings suggest a new paradigm for microRNA-based control of ligand-receptor interactions and provide evidence for a novel signaling pathway regulating vertebrate heart tube assembly.