Recovery at 30: Perspectives from Psychiatry Clinicians and Senior Faculty.

According to William Anthony's "Recovery from mental illness: the guiding vision of the mental health service system in the 1990s," mental health recovery means "changing one's attitudes, values, feelings, goals, and skills in order to live a satisfying life within the limitations caused by illness." This seminal work served as an overarching goal, a call to action, and a roadmap for the enhancement of psychiatric recovery. Unfortunately, from many viewpoints, the goals encouraged by Anthony have not been achieved. Through semi-structured interviews with psychiatry clinicians and senior faculty members, this article aims to elucidate the current status of psychiatric recovery, how the movement progressed to this point, and where we could go from here. The development of the recovery movement will be discussed, along with its assumptions and explicit goals. The interviews focus on the extent to which these goals have been achieved, barriers to progress, whether goals should be revised, and how to achieve these goals.

Psychometrics of Three Dissociation Scales: Reliability and Validity Data on the DESR, DES-II, and DESC.

The current study assessed the reliability and validity of three measures of dissociation. Three hundred students completed the Dissociative Experiences Scale Revised (DESR), the Dissociative Experiences Scale-II (DES-II), and the Dissociative Experiences Scale Comparison (DESC); an additional 252 community adults evaluated clarity of instructions. Findings revealed that the three dissociation measures showed acceptable test-retest reliability and Cronbach's alphas. The DESR and DES-II strongly intercorrelated, but the DESC correlated only moderately with the two remaining dissociation measures, sharing less than 10% of the variance with the original scale. Additionally, the DESR and DES-II showed stronger convergent validity (correlation with measures of alexithymia and post-traumatic stress disorder) than did the DESC. The DESC was the only measure unrelated to trauma history. Participants reported substantially greater difficulty in understanding and utilizing the metric offered by the DESC. In conclusion, evidence supports the DES-II and DESR as alternate measures, but the DESC requires more investigation.

The Paired-box protein PAX-3 regulates the choice between lateral and ventral epidermal cell fates in C. elegans.

The development of the single cell layer skin or hypodermis of Caenorhabditis elegans is an excellent model for understanding cell fate specification and differentiation. Early in C. elegans embryogenesis, six rows of hypodermal cells adopt dorsal, lateral or ventral fates that go on to display distinct behaviors during larval life. Several transcription factors are known that function in specifying these major hypodermal cell fates, but our knowledge of the specification of these cell types is sparse, particularly in the case of the ventral hypodermal cells, which become Vulval Precursor Cells and form the vulval opening in response to extracellular signals. Previously, the gene pvl-4 was identified in a screen for mutants with defects in vulval development. We found by whole genome sequencing that pvl-4 is the Paired-box gene pax-3, which encodes the sole PAX-3 transcription factor homolog in C. elegans. pax-3 mutants show embryonic and larval lethality, and body morphology abnormalities indicative of hypodermal cell defects. We report that pax-3 is expressed in ventral P cells and their descendants during embryogenesis and early larval stages, and that in pax-3 reduction-of-function animals the ventral P cells undergo a cell fate transformation and express several markers of the lateral seam cell fate. Furthermore, forced expression of pax-3 in the lateral hypodermal cells causes them to lose expression of seam cell markers. We propose that pax-3 functions in the ventral hypodermal cells to prevent these cells from adopting the lateral seam cell fate. pax-3 represents the first gene required for specification solely of the ventral hypodermal fate in C. elegans providing insights into cell type diversification.

C. elegans GATA factors EGL-18 and ELT-6 function downstream of Wnt signaling to maintain the progenitor fate during larval asymmetric divisions of the seam cells.

The C. elegans seam cells are lateral epithelial cells arrayed in a single line from anterior to posterior that divide in an asymmetric, stem cell-like manner during larval development. These asymmetric divisions are regulated by Wnt signaling; in most divisions, the posterior daughter in which the Wnt pathway is activated maintains the progenitor seam fate, while the anterior daughter in which the Wnt pathway is not activated adopts a differentiated hypodermal fate. Using mRNA tagging and microarray analysis, we identified the functionally redundant GATA factor genes egl-18 and elt-6 as Wnt pathway targets in the larval seam cells. EGL-18 and ELT-6 have previously been shown to be required for initial seam cell specification in the embryo. We show that in larval seam cell asymmetric divisions, EGL-18 is expressed strongly in the posterior seam-fated daughter. egl-18 and elt-6 are necessary for larval seam cell specification, and for hypodermal to seam cell fate transformations induced by ectopic Wnt pathway overactivation. The TCF homolog POP-1 binds a site in the egl-18 promoter in vitro, and this site is necessary for robust seam cell expression in vivo. Finally, larval overexpression of EGL-18 is sufficient to drive expression of a seam marker in other hypodermal cells in wild-type animals, and in anterior hypodermal-fated daughters in a Wnt pathway-sensitized background. These data suggest that two GATA factors that are required for seam cell specification in the embryo independently of Wnt signaling are reused downstream of Wnt signaling to maintain the progenitor fate during stem cell-like divisions in larval development.

Flavonoids from each of the six structural groups reactivate BRM, a possible cofactor for the anticancer effects of flavonoids.

Flavonoids have been extensively studied and are well documented to have anticancer effects, but it is not entirely known how they impact cellular mechanisms to elicit these effects. In the course of this study, we found that a variety of different flavonoids readily restored Brahma (BRM) in BRM-deficient cancer cell lines. Flavonoids from each of the six different structural groups were effective at inducing BRM expression as well as inhibiting growth in these BRM-deficient cancer cells. By blocking the induction of BRM with shRNA, we found that flavonoid-induced growth inhibition was BRM dependent. We also found that flavonoids can restore BRM functionality by reversing BRM acetylation. In addition, we observed that an array of natural flavonoid-containing products both induced BRM expression as well as deacetylated the BRM protein. We also tested two of the BRM-inducing flavonoids (Rutin and Diosmin) at both a low and a high dose on the development of tumors in an established murine lung cancer model. We found that these flavonoids effectively blocked development of adenomas in the lungs of wild-type mice but not in that of BRMnull mice. These data demonstrate that BRM expression and function are regulated by flavonoids and that functional BRM appears to be a prerequisite for the anticancer effects of flavonoids both in vitro and in vivo.

Optimized Workflow from Gene to Product.

This chapter outlines the workflow using the ExpiSf™ Expression System designed for high-density infection of suspension ExpiSf9™ cells. The system utilizes a chemically defined, serum-free, protein-free, and animal origin free medium, making it suitable for recombinant protein expression experiments. The ExpiSf™ chemically defined medium allows efficient transfection and baculovirus production directly within the same culture medium. The ExpiSf™ Expression System Starter Kit provides all necessary components, including cells, culture medium, and reagents needed to infect one (1) liter of cell culture. The system's versatility and animal origin free nature make it a valuable tool for various protein expression studies and biotechnological applications.

TOPO Cloning for Efficient Plasmid Construction.

This chapter outlines the use of TOPO cloning for streamlined generation of a recombinant plasmid containing your gene of interest for use in the Bac-to-Bac™ Baculovirus Expression System.

Rapid Two-Day Baculovirus Titering Using Flow Cytometry.

This chapter outlines a rapid detection method to determine the virus titer of your baculovirus stock. Staining of cells with fluorescently labeled gp64 antibody allows for flow cytometer-based quantitation of baculovirus-infected insect cells. In this assay, Sf9 cells are infected with tenfold serial dilutions of the test virus stock, and baculovirus titers are calculated based on the ratio of infected to uninfected cells 13 to 18 h after inoculation.

PERK modulation, with GSK2606414, Sephin1 or salubrinal, failed to produce therapeutic benefits in the SOD1G93A mouse model of ALS.

Amyotrophic lateral sclerosis (ALS) has been linked to overactivity of the protein kinase RNA-like ER kinase (PERK) branch of the unfolded protein response (UPR) pathway, both in ALS patients and mouse models. However, attempts to pharmacologically modulate PERK for therapeutic benefit have yielded inconsistent and often conflicting results. This study sought to address these discrepancies by comprehensively evaluating three commonly used, CNS-penetrant, PERK modulators (GSK2606414, salubrinal, and Sephin1) in the same experimental models, with the goal of assessing the viability of targeting the PERK pathway as a therapeutic strategy for ALS. To achieve this goal, a tunicamycin-challenge assay was developed using wild-type mice to monitor changes in liver UPR gene expression in response to PERK pathway modulation. Subsequently, multiple dosing regimens of each PERK modulator were tested in standardized, well-powered, gender-matched, and litter-matched survival efficacy studies using the SOD1G93A mouse model of ALS. The alpha-2-adrenergic receptor agonist clonidine was also tested to elucidate the results obtained from the Sephin1, and of the previously reported guanabenz studies, by comparing the effects of presence or absence of α-2 agonism. The results revealed that targeting PERK may not be an ideal approach for ALS treatment. Inhibiting PERK with GSK2606414 or activating it with salubrinal did not confer therapeutic benefits. While Sephin1 showed some promising therapeutic effects, it appears that these outcomes were mediated through PERK-independent mechanisms. Clonidine also produced some favorable therapeutic effects, which were unexpected and not linked to the UPR. In conclusion, this study highlights the challenges of pharmacologically targeting PERK for therapeutic purposes in the SOD1G93A mouse model and suggests that exploring other targets within, and outside, the UPR may be more promising avenues for ALS treatment.

Garnering partnerships to bridge gaps among mental health, health care, and public health.

Integrating mental health and public health chronic disease programs requires partnerships at all government levels. Four examples illustrate this approach: 1) a federal partnership to implement mental health and mental illness modules in the Behavioral Risk Factor Surveillance System; 2) a state partnership to improve diabetes health outcomes for people with mental illness; 3) a community-level example of a partnership with local aging and disability agencies to modify a home health service to reduce depression and improve quality of life among isolated, chronically ill seniors; and 4) a second community-level example of a partnership to promote depression screening and management and secure coverage in primary care settings. Integration of mental health and chronic disease public health programs is a challenging but essential and achievable task in protecting Americans' health.

The perils of practicum in the time of COVID-19: A graduate student's perspective.

The COVID-19 pandemic has placed competing demands on many graduate students working at practica. Though graduate programs seek to minimize potential sources of exposure to the virus, some practicum sites rely on students as essential staff. At the same time, although some students may wish to eliminate this source of potential exposure to the virus, other students may consider the opportunity to fulfill their practicum duties at a time of crisis an important part of their educational experience. Guidance published by the Association of Psychology Postdoctoral and Internship Centers regarding internship students provides at least a starting point for programs to develop policies that allow students to make informed decisions about their practicum training. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Perceived Benefits of Anatomy Coursework Prior to Medical and Dental School.

Student struggles in gross anatomy coursework at the professional level can result in hours of remediation along with a need to allot time and other resources by both the student and the faculty. Since this course typically occurs in the first semester of the first year, programs can turn to admissions data to try to determine which of these students may struggle. This study looked at two years of medical (n = 280) and dental (n = 78) students to determine if there is a relationship between pre-admissions anatomy coursework and performance in gross anatomy at the professional school level. Students provided data regarding their past anatomy coursework and final grades in professional school gross anatomy courses were obtained. In addition, students responded to questions regarding their feelings of preparation and how they valued the prior anatomy coursework as it related to the professional course. Statistical analysis showed no difference in final course grade between students with and without prior anatomy in either program. Counter to the numerical data, 96.6% of the students in the study recommended an anatomy course prior to pursuing a health science degree. The primary reasons given for this recommendation were the benefits of repeated content exposure, knowledge of the anatomy terminology, and decreased stress regarding the course. The results from this study suggest that the benefits of prior anatomy may be seen more in the students' stress and quality of life rather in the numerical performance of course grades.

Improving protein structure similarity searches using domain boundaries based on conserved sequence information.

BACKGROUND: The identification of protein domains plays an important role in protein structure comparison. Domain query size and composition are critical to structure similarity search algorithms such as the Vector Alignment Search Tool (VAST), the method employed for computing related protein structures in NCBI Entrez system. Currently, domains identified on the basis of structural compactness are used for VAST computations. In this study, we have investigated how alternative definitions of domains derived from conserved sequence alignments in the Conserved Domain Database (CDD) would affect the domain comparisons and structure similarity search performance of VAST. RESULTS: Alternative domains, which have significantly different secondary structure composition from those based on structurally compact units, were identified based on the alignment footprints of curated protein sequence domain families. Our analysis indicates that domain boundaries disagree on roughly 8% of protein chains in the medium redundancy subset of the Molecular Modeling Database (MMDB). These conflicting sequence based domain boundaries perform slightly better than structure domains in structure similarity searches, and there are interesting cases when structure similarity search performance is markedly improved. CONCLUSION: Structure similarity searches using domain boundaries based on conserved sequence information can provide an additional method for investigators to identify interesting similarities between proteins with known structures. Because of the improvement in performance of structure similarity searches using sequence domain boundaries, we are in the process of implementing their inclusion into the VAST search and MMDB resources in the NCBI Entrez system.

Norfloxacin treatment for clinically significant portal hypertension: results of a randomised double-blind placebo-controlled crossover trial.

BACKGROUND: While selective intestinal decontamination (SID) can alter the hyperdynamic circulatory state of cirrhosis, the impact of SID on portal pressure remains unclear especially in the setting of clinically significant portal hypertension. AIMS: To examine the impact of SID with norfloxacin on portal pressure in subjects with clinically significant portal hypertension and explore the potential mechanisms by which norfloxacin exerts its haemodynamic effects. METHODS: Randomised, double blind, placebo-controlled, crossover trial of norfloxacin 400 mg twice daily for 4 weeks. The portal pressure was assessed by hepatic venous pressure gradient (HVPG). Endotoxaemia was assessed by the Limulus amebocyte lysate (LAL) assay. l-arginine (l-Arg) transporter function was assessed in peripheral blood mononuclear cells (PBMCs). Plasma levels of urotensin II (UII) and tumour necrosis factor were measured before and after therapy. RESULTS: Sixteen subjects with clinically significant portal hypertension (16.5+/-1.1 mmHg) completed the study. Norfloxacin therapy was not superior to placebo in reducing HVPG (13.8+/-1.0 mmHg vs 13.6+/-1.2 mmHg, P=0.3). Furthermore, no alteration in l-Arg transport was detected after 4 weeks of norfloxacin therapy. Plasma UII levels correlated positively with HVPG (P=0.01) and the Child-Pugh score (P<0.05). However, UII levels following therapy did not parallel HVPG changes. CONCLUSIONS: Norfloxacin is not superior to placebo in reducing HVPG in subjects with clinically significant portal hypertension. Furthermore, norfloxacin does not appear to modulate the l-Arg transporter mechanism in this patient population. Although plasma UII correlates positively with HVPG, UII does not appear to have a direct role in modulating HVPG.

Prosection or Dissection: Which is Best for Teaching the Anatomy of the Hand and Foot?

Due to the current trend of decreasing contact hours and less emphasis being given to the basic science courses in the pre-clinical years of medical education, it is essential that new approaches to teaching gross anatomy are investigated to ensure medical students are being adequately exposed to anatomical content. This study retrospectively analyzed practical examination data from four medical gross anatomy classes (N = 569) to ascertain which pedagogical approach, student participation in the dissection process, or interaction with prosected specimens is best for teaching the anatomy of the hand and foot. Data analysis involved the use of propensity score matching, a nonparametric preprocessing statistical approach which ensures accurate representation of the true treatment effect by balancing cohorts prior to statistical analysis. Statistical analysis indicated that those students who were exposed to the anatomy of the hand through interactions with prosected specimens performed 5.6% better (P = 0.012) while for the foot, students who interacted with prosections performed 13.0% better (P < 0.001). Although limited, data from this study suggest that utilizing prosections of the hand and foot seems to be a more advantageous pedagogical approach for teaching these regions than requiring students to dissect them.

Freshwater microalgae (Schizochytrium sp.) as a substitute to fish oil for shrimp feed.

Micro-algae, Schizochytrium sp., is rich source of docosahexaenoic acid, DHA (66%-lipid with 27%-DHA). Eight nutritionally balanced-diets were formulated: diet 1 (control) consisted of only fish oil (FO); diets 2 and 3 had increasing amounts of algae-meal and soybean oil (SBO) at the expense of FO; diet 4 consisted of a combination of algae meal (37-g/kg), SBO (21-g/kg), and linseed oil (LSO) at 4-g/kg each; diet 5 had microalgae meal at 50-g/kg and equal amounts of LSO and SBO at 8-g/kg; diets 6 and 7 contained equal amounts of algae-meal at 62-g/kg, but with LSO or SBO added at 8-mg/g, respectively; diet 8 contained only algae-meal at 75-mg/g. Growth and feeding efficiencies of L. vannamei were not significantly different among treatments. Fatty acid composition of muscle generally reflected that of the diet. The amount of muscle sub-epidermal adipose tissue was significantly higher for shrimp fed diets 3 and 7, while intestinal lipase was significantly higher in shrimp fed diets 7 and 8. Muscle lipid peroxidation was unaffected by the dietary treatments, although antioxidant activities were significantly higher in shrimp fed diet 7 compared to those fed diet 1. Overall algal-meal can completely replace the FO in shrimp feed.

SOD1-positive aggregate accumulation in the CNS predicts slower disease progression and increased longevity in a mutant SOD1 mouse model of ALS.

Non-natively folded variants of superoxide dismutase 1 (SOD1) are thought to contribute to the pathogenesis of familial amyotrophic lateral sclerosis (ALS), however the relative toxicities of these variants are controversial. Here, we aimed to decipher the relationships between the different SOD1 variants (aggregated, soluble misfolded, soluble total) and the clinical presentation of ALS in the SOD1G93A mouse. Using a multi-approach strategy, we found that the CNS regions least affected by disease had the most aggregated SOD1. We also found that the levels of aggregated SOD1 in the spinal cord were inversely correlated with the disease progression. Conversely, in the most affected regions, we observed that there was a high soluble misfolded/soluble total SOD1 ratio. Taken together, these findings suggest that soluble misfolded SOD1 may be the disease driver in ALS, whereas aggregated SOD1 may serve to sequester the toxic species acting in a neuroprotective fashion.

Severe eczema vaccinatum in a household contact of a smallpox vaccinee.

BACKGROUND: We report the first confirmed case of eczema vaccinatum in the United States related to smallpox vaccination since routine vaccination was discontinued in 1972. A 28-month-old child with refractory atopic dermatitis developed eczema vaccinatum after exposure to his father, a member of the US military who had recently received smallpox vaccine. The father had a history of inactive eczema but reportedly reacted normally to the vaccine. The child's mother also developed contact vaccinia infection. METHODS: Treatment of the child included vaccinia immune globulin administered intravenously, used for the first time in a pediatric patient; cidofovir, never previously used for human vaccinia infection; and ST-246, an investigational agent being studied for the treatment of orthopoxvirus infection. Serological response to vaccinia virus and viral DNA levels, correlated with clinical events, were utilized to monitor the course of disease and to guide therapy. Burn patient-type management was required, including skin grafts. RESULTS: The child was discharged from the hospital after 48 days and has recovered with no apparent systemic sequelae or significant scarring. CONCLUSION: This case illustrates the need for careful screening prior to administration of smallpox vaccine and awareness by clinicians of the ongoing vaccination program and the potential risk for severe adverse events related to vaccinia virus.

Design, power, and interpretation of studies in the standard murine model of ALS.

Identification of SOD1 as the mutated protein in a significant subset of familial amyotrophic lateral sclerosis (FALS) cases has led to the generation of transgenic rodent models of autosomal dominant SOD1 FALS. Mice carrying 23 copies of the human SOD1(G93A) transgene are considered the standard model for FALS and ALS therapeutic studies. To date, there have been at least 50 publications describing therapeutic agents that extend the lifespan of this mouse. However, no therapeutic agent besides riluzole has shown corresponding clinical efficacy. We used computer modeling and statistical analysis of 5429 SOD1(G93A) mice from our efficacy studies to quantify the impact of several critical confounding biological variables that must be appreciated and should be controlled for when designing and interpreting efficacy studies. Having identified the most critical of these biological variables, we subsequently instituted parameters for optimal study design in the SOD1(G93A) mouse model. We retested several compounds reported in major animal studies (minocycline, creatine, celecoxib, sodium phenylbutyrate, ceftriaxone, WHI-P131, thalidomide, and riluzole) using this optimal study design and found no survival benefit in the SOD1(G93A) mouse for any compounds (including riluzole) administered by their previously reported routes and doses. The presence of these uncontrolled confounding variables in the screening system, and the failure of these several drugs to demonstrate efficacy in adequately designed and powered repeat studies, leads us to conclude that the majority of published effects are most likely measurements of noise in the distribution of survival means as opposed to actual drug effect. We recommend a minimum study design for this mouse model to best address and manage this inherent noise and to facilitate more significant and reproducible results among all laboratories employing the SOD1(G93A) mouse.

American Association of Community Psychiatrists' views on general features of DSM-IV.

OBJECTIVE: The authors report on a survey of the American Association of Community Psychiatrists (AACP) about improving DSM-IV. METHODS: An anonymous survey was sent to 600 psychiatrists of the AACP via Survey Monkey technology. RESULTS: Respondents (N=152) answered questionnaires regarding the general features of DSM-IV. Reliable interclinician communication was valued most highly. A majority of respondents (92%) reported using axis 1, 75% used axes 2 and 3, and approximately 50% used axes 4 and 5. AACP members were less keen on using the tool to inform patient management planning. Least valued were usefulness for a national statistical base or to indicate prognosis. CONCLUSIONS: AACP respondents' views suggest modification to the DSM system to improve clinical utility. Most favored fewer than 100 diagnostic categories. Many were concerned about the current systems' cultural sensitivity and accessibility to patients. These considerations should guide DSM-V deliberations.