Title: Obesogenic microbial signatures and the development of obesity in childhood acute lymphoblastic leukemia.

Childhood acute lymphoblastic leukemia (ALL) is the most common childhood cancer with survival exceeding 90% for standard-risk groups. A debilitating side-effect of treatment is the development of overweight/obesity (OW/OB), which develops in approximately 40% of children by the end of treatment. The microbiome has been associated with the development of OW/OB. We examined fluctuations in the microbiome with the development of OW/OB during the first six months of treatment at diagnosis, and two subsequent timepoints (N = 62). Shotgun metagenomic sequencing was performed on Illumina Nextseq system, and taxa and functional pathways were extracted from sequences using kraken2 and humann2, respectively. An association of increased presence of several species (e.g., Klebsiella pneumoniae, Escherichia coli) was observed in children with OW/OB, while lean-promoting species (Veillonella, Haemophilus, and Akkermansia) were increased in children who maintained a normal weight. Pathway analysis revealed purine nucleotide biosynthesis, sugar nucleotide biosynthesis, and enzyme cofactor biosynthesis were positively correlated with Bacteroides spp. among children with OW/OB. We identified several taxa and functional pathways that may confer increased risk for the development of OW/OB. The associations observed in this pilot are preliminary and warrant further research in the microbiome and the development of OW/OB in childhood ALL.

Antileishmanial Aminopyrazoles: Studies into Mechanisms and Stability of Experimental Drug Resistance.

Current antileishmanial treatment is hampered by limitations, such as drug toxicity and the risk of treatment failure, which may be related to parasitic drug resistance. Given the urgent need for novel drugs, the Drugs for Neglected Diseases initiative (DNDi) has undertaken a drug discovery program, which has resulted in the identification of aminopyrazoles, a highly promising antileishmanial chemical series. Multiple experiments have been performed to anticipate the propensity for resistance development. Resistance selection was performed by successive exposure of Leishmania infantum promastigotes (in vitro) and intracellular amastigotes (both in vitro and in golden Syrian hamsters). The stability of the resistant phenotypes was assessed after passage in mice and Lutzomyia longipalpis sandflies. Whole-genome sequencing (WGS) was performed to identify mutated genes, copy number variations (CNVs), and somy changes. The potential role of efflux pumps (the MDR and MRP efflux pumps) in the development of resistance was assessed by coincubation of aminopyrazoles with specific efflux pump inhibitors (verapamil, cyclosporine, and probenecid). Repeated drug exposure of amastigotes did not result in the emergence of drug resistance either in vitro or in vivo Selection at the promastigote stage, however, was able to select for parasites with reduced susceptibility (resistance index, 5.8 to 24.5). This phenotype proved to be unstable after in vivo passage in mice and sandflies, suggesting that nonfixed alterations are responsible for the elevated resistance. In line with this, single nucleotide polymorphisms and indels identified by whole-genome sequencing could not be directly linked to the decreased drug susceptibility. Copy number variations were absent, whereas somy changes were detected, which may have accounted for the transient acquisition of resistance. Finally, aminopyrazole activity was not influenced by the MDR and MRP efflux pump inhibitors tested. The selection performed does not suggest the rapid development of resistance against aminopyrazoles in the field. Karyotype changes may confer elevated levels of resistance, but these do not seem to be stable in the vertebrate and invertebrate hosts. MDR/MRP efflux pumps are not likely to significantly impact the activity of the aminopyrazole leads.

In vitro and in vivo pharmacodynamics of three novel antileishmanial lead series.

OBJECTIVES: Three new chemical series (bicyclic nitroimidazoles, aminopyrazoles and oxaboroles) were selected by Drugs for Neglected Diseases initiative as potential new drug leads for leishmaniasis. Pharmacodynamics studies included both in vitro and in vivo efficacy, cross-resistance profiling against the current antileishmanial reference drugs and evaluation of their cidal activity potential. METHODS: Efficacy against the reference laboratory strains of Leishmania infantum (MHOM/MA(BE)/67/ITMAP263) and L. donovani (MHOM/ET/67/L82) was evaluated in vitro on intracellular amastigotes and in vivo in the early curative hamster model. Cidal activity was assessed over a period of 15 days in an in vitro 'time-to-kill' assay. Cross-resistance was assessed in vitro on a panel of L. infantum strains with different degrees of resistance to either antimony, miltefosine or paromomycin. RESULTS: All lead compounds showed potent and selective in vitro activity against the Leishmania strains tested and no cross-resistance could be demonstrated against any of the current antileishmanial drugs. Cidal activity was obtained in vitro for all series within 15 days of exposure with some differences noted between L. donovani and L. infantum. When evaluated in vivo, all lead compounds showed high efficacy and no adverse effects were observed. CONCLUSIONS: The new lead series were shown to have cidal pharmacodynamic activity. The absence of cross-resistance with any of the current antileishmanial drugs opens possibilities for combination treatment to reduce the likelihood of treatment failures and drug resistance.

Mitochondrial DNA haplogroups and type 2 diabetes: a study of 897 cases and 1010 controls.

Mitochondria play a central role in the secretion of insulin by pancreatic beta-cells, and pathogenic mutations of mitochondrial DNA (mtDNA) can cause diabetes. The aetiology of type 2 diabetes has a strong genetic component, raising the possibility that genetic variants of mtDNA alter the risk of developing the disorder. Recent studies have produced conflicting results. By studying 897 UK cases of type 2 diabetes and 1010 population-matched controls, it is shown that European mtDNA haplogroups are unlikely to play a major role in the risk of developing the disorder.

Raising our sites: dissemination of supported education.

In order to promote replication of supported education, an exemplary rehabilitation model for adults with psychiatric disabilities, funds were accessed through a Community Action Grant from the Center for Mental Health Services of the Substance Abuse and Mental Health Services Administration. Three communities in Michigan participated in a multistage process designed to maximize community ownership by encouraging local adaptations involving all stakeholder groups and providing technical assistance. The stages in the process were organizing the community for supported education development, acquiring knowledge about supported education basics, collecting information (needs assessment and barrier identification), and developing the plan. All three sites have begun implementation, providing services to adults with psychiatric disabilities who wish to pursue post-secondary education. The approach employed has applicability for other local communities.

Expression of BMP signalling pathway members in the developing zebrafish inner ear and lateral line.

In this paper we describe the mRNA expression patterns of members of the bone morphogenetic protein (BMP) signalling pathway in the developing zebrafish ear. bmp2b, 4, and 7 are expressed in discrete areas of otic epithelium, some of which correspond to sensory patches. bmp2b and 4 mark the developing cristae before and during the appearance of differentiated hair cells. bmp4 is also expressed in a dorsal, non-sensory region of the ear. Expression of bmps in cristae is conserved between zebrafish, chick, and mouse, but there are also notable differences in ear expression patterns between these species. Of five zebrafish BMP antagonists, only one (follistatin) shows significant expression in the otic epithelium. The type I receptor bmpr-IB shows localised expression in the ear epithelium. Mediators of BMP signalling, smad1 and smad5, are expressed in statoacoustic and lateral line ganglia; smad5 is also expressed at low levels throughout the ear epithelium. An inhibitory smad, smad6, is expressed laterally in the ear epithelium. Lateral line primordia and neuromasts also express bmp2b, 4, follistatin, smad1, and smad5. The conservation of bmp expression in cristae among different species adds weight to the growing evidence that BMPs are required for the development of the vertebrate ear.

The IAPSRS toolkit: development, utility, and relation to other performance measurement systems. Members of the IAPSRS Research Committee. International Association of Psychological Rehabilitation Services.

The current climate of economic constraint in community-based mental health services has all but required psychosocial rehabilitation (PSR) programs to demonstrate their effectiveness by adopting outcome assessment systems. Agencies of disparate size and varying degrees of sophistication are now responding to mandates to systematically monitor program outcomes. In doing so, however, PSR practitioners and administrators are faced with a bewildering array of competing measures, some of which are impractical, costly, or irrelevant for capturing the outcomes of PSR services (Blankertz & Cook, 1998). To acquaint readers with issues in performance measurement in PSR, this article describes a newly developed outcome measurement system created to document the achievements of service recipients in PSR programs and to monitor progress towards recovery. We discuss principles and logistical issues in performance measurement which are important to PSR agencies and which the Toolkit has been designed to address. Results of the pilot testing of the PSR Toolkit are presented to demonstrate the feasibility of its use, logistical problems in implementation, psychometric properties of the measures, and the Toolkit's sensitivity to change. We discuss next steps in the development of the Toolkit.

Structure-activity relationships of 1,4-dihydro-(1H,4H)-quinoxaline-2,3-diones as N-methyl-D-aspartate (glycine site) receptor antagonists. 1. Heterocyclic substituted 5-alkyl derivatives.

A series of 6,7-dichloro-1,4-dihydro-(1H, 4H)-quinoxaline-2,3-diones (1-17) were prepared in which the 5-position substituent was a heterocyclylmethyl or 1-(heterocyclyl)-1-propyl group. Structure-activity relationships were evaluated where binding affinity for the glycine site of the N-methyl-D-aspartate (NMDA) receptor was measured using the specific radioligand [3H]-L-689,560, and functional antagonism was demonstrated by inhibition of NMDA-induced depolarizations of rat cortical wedges. The ability to prevent NMDA-induced hyperlocomotion in mice in vivo was measured for selected compounds. Binding affinity increased significantly if the heterocyclic group, e.g. 1,2,3-triazol-1-yl could participate in accepting a hydrogen bond from the receptor. It was difficult to obtain compounds with adequate aqueous solubility and strategies to improve it were investigated. The most potent compound in this series, 6,7-dichloro-5-[1-(1,2,4-triazol-4-yl)propyl]-1,4-dihydro-(1H, 4H)-quinoxaline-2,3-dione (17) (binding IC50 = 2.6 nM; cortical wedge EC50 = 90 nM), inhibited NMDA-induced hyperlocomotion in mice (6/9 protected at 20 mg/kg iv). Pharmacokinetic parameters, including extent of brain penetration, for 11 and 17 are reported.

Follow-up client satisfaction in a supported education program.

Satisfaction data have recently returned to popularity, as an outcome measure in managed behavioral healthcare systems. However, there are few examples of management uses of such data. We collected data 12 months after participants had completed a supported education program, concerning their retrospective satisfaction and the barriers, needs, and personal difficulties currently experienced in their attempts to pursue post-secondary education or training. Data on follow-up supportive contacts were also obtained. Results supported participants' continuing satisfaction, and identified particular information items which were endorsed as most helpful. However, the data indicated that personal difficulties presented obstacles to many and that a majority of participants had current needs for financial aid, tutoring, job placements, support groups, and transportation. Following completion of the supported education program, many participants had continuing contacts in support of their educational plans. The amount of contact was generally low, however. In the future, supported education programs need to build in mechanisms to ensure students receive ongoing support for education, since this support was found to positively and significantly affect individuals' enrolling in college or training.

Life circumstances of mothers with serious mental illnesses.

Individuals with a severe mental illness now have greater opportunities to pursue normal adult roles, including parenting. The research reported involved 379 women carrying out parenting responsibilities, recruited from the public mental health system in an urban area. The sample displayed great heterogeneity in educational levels, number of children, number of fathers for their children, and family living arrangements, except that most women were very poor. These women faced many significant stresses: living alone with their children, significant child behavior problems, and financial worries. Still, most of the women endorsed the significance of motherhood in their lives. Inattention by most mental health providers to parenting issues leaves many important needs unmet and is likely to have adverse consequences for these women and their children. Implications for psychosocial rehabilitation practice are discussed.

The Michigan Supported Education Program.

With the advent of improved pharmacological treatments, empirically tested psychiatric rehabilitation techniques, and an increased emphasis on the empowerment of mental health consumers, many adults with psychiatric disabilities now have a realistic chance of reentering their communities and reestablishing meaningful and productive lives. Because work is a fundamental component of adjustment in adult life, helping individuals obtain and maintain jobs has been viewed as the sine qua non of psychiatric rehabilitation. More recently, however, rehabilitation practitioners have realized that many adults with psychiatric disabilities have the desire and the requisite motivation and educational background to attend college (1). Hence rehabilitation practitioners have recognized that helping individuals restart their postsecondary educational pursuits is a desirable, valid, and viable option (2,3). Supported education is being used increasingly to encourage adults with mental illness to enroll in and complete postsecondary education by providing assistance, preparation, and ongoing counseling (4). Several reports have suggested that supported education programs contribute to positive outcomes such as graduation, acquisition of marketable skills, employment, and positive self-esteem (5,6,7). In this month's column, Carol Mowbray, Ph.D., describes the Michigan Supported Education Program and provides a rationale and empirical validation for its inclusion as an integral modality of psychiatric rehabilitation.

Longitudinal effects of integrated treatment on alcohol use for persons with serious mental illness and substance use disorders.

A randomized experimental design was used to assign participants to an integrated mental health and substance use treatment program or to standard hospital treatment. A multilevel, nonlinear model was used to estimate hospital treatment effects on days of alcohol use for persons with serious mental illness and substance use disorders over 18 months. The integrated treatment program had a significant effect on the rate of alcohol use at 2 months postdischarge, reducing the rate of use by 54%. Motivation for sobriety at hospital discharge, posttreatment self-help attendance, and social support for sobriety were also found to reduce the rate of use during the follow-up period. Implications for mental health treatment and aftercare support are discussed.

Parenting among mothers with a serious mental illness.

In the past few decades, deinstitutionalization and community-based rehabilitation and support programs have increased the likelihood that women with serious mental disorders will be parents and will raise their children. This review describes what is known about the parenting of these women, focusing on diagnosis, child characteristics, and other contextual effects.

Characteristics predicting successful outcomes of participants with severe mental illness in supported education.

OBJECTIVE: The study sought to identify characteristics of participants in a supported education program that were related to a successful outcome. Supported education programs provide rehabilitation and support services to help people attain postsecondary education. METHODS: A total of 147 persons who completed such a program were interviewed six or 12 months later, or at both times, to determine whether they were involved in productive activity, which was defined as engaging in either college or vocational education or in paid employment. Variables examined as predictors of productive activity were demographic characteristics; education and work background; social support; self-perceptions related to self-esteem, empowerment, quality of life, and school self-efficacy; and illness-related variables, including diagnosis, symptoms, and length of illness. RESULTS: Multivariate logistic regression identified the strongest predictor as productive activity at baseline. Marital status was the only significant demographic variable in the model; single participants were less likely to be engaged in productive activity. For participants who reported more frequent contact with their social network, the likelihood of engagement in productive activity was higher, and for those who reported more encouragement for education from their network, the likelihood was lower. A lower level of adjustment in the financial domain decreased the likelihood of productive activity, and a higher level of problems with housework increased the likelihood. No illness-related variable or self-perception was a significant predictor. CONCLUSIONS: Factors related to a successful outcome from a supported education program for persons with severe mental illness are also likely to be important factors for nondisabled populations. Among those with mental illness, social support is a key factor in attaining educational and vocational goals.

Mothers with serious mental illness.

Mental health services have generally ignored the parenting needs of women with serious mental illness. This chapter identifies the parenting risks and strengths that these women display, as well as the opportunities available to psychologists to play a key role in improving mother and child outcomes.

Integrating vocational services on case management teams: outcomes from a research demonstration project.

Recent innovations to improve employment rates among persons with psychiatric disabilities include "hybrid case management/employment services." Project WINS was a research/demonstration project which integrated specialized vocational services into case management teams. In this report, client outcomes of WINS involvement are evaluated, using a quasiexperimental, longitudinal design. On almost all the work-related variables, participants in the immediate and delayed treatment conditions displayed better outcomes than those in the control condition, as did individuals receiving moderate or substantial service versus no/ minimal services. To address possible selection bias due to the quasiexperimental nature of the design, further analyses used baseline differences across conditions and participation levels as covariates. Results of multivariate analyses showed some anomalous findings regarding significant positive effects for the delayed, but not the immediate treatment condition versus the no-treatment control group. However, in similar analyses involving participation level as the independent variable, a moderate or substantial amount of service increased the odds of working by almost five times and also positively affected three other work-related variables. While limitations of this quasiexperimental design are noted, the results appear promising enough to support replications of WINS.

Measuring coping strategies in an educational intervention for individuals with psychiatric disabilities.

Coping is a critical theoretical concept believed to be a mediator for successful outcomes produced through a variety of different social work interventions. This article describes an approach used to measure coping with stressors and was designed specifically for an intervention, the Michigan Supported Education Research Project, aimed at providing support for people with psychiatric disabilities to pursue college or vocational education. Hypothetical scenarios were developed that matched the content of material covered in the program. Open-ended responses were elicited from program participants as part of an in-person interview. Key findings included a participation effect on the number of positive coping strategies of participants and a significant relationship among some coping strategies and later outcomes. Implications for social work practice and research are identified.

Analysis of postdischarge change in a dual diagnosis population.

Many individuals with serious mental illnesses have co-occurring drug and alcohol problems. The research reported in this article examined an integrated inpatient mental illness-chemical dependency program and compared it with standard inpatient psychiatric treatment for two groups: those demonstrating high change from baseline to two-months postdischarge and those with negative or no change. Univariate analyses revealed significant differences in the change groups on baseline personal-clinical characteristics and on aspects of their social and physical environments. The results have implications for improving mental health practice by better predicting patients who will optimally benefit from inpatient treatment.

Mental illness and substance abuse: implications for women's health and health care access.

Individuals with serious mental illness (SMI) and/or alcohol and other drug (AOD) problems often have physical health concerns that are not appropriately treated and that interfere with effective management of SMI and/or AOD problems and contribute to the overall costs to society of these disorders. Although the literature has limitations, available evidence suggests that women with SMI and/or AOD problems have more numerous and severe health concerns than comparable men and that they receive less appropriate health care than men do. These greater problems relate directly to SMI or AOD use, or involve difficulties in complying with medical regimens, side effects of medications, or interactions of AOD use and SMI with other health conditions. Individuals' life situations can also increase their vulnerabilities and health risks. Health problems frequently are not detected by specialty or general practice health professionals, and thus get worse. Women with SMI and AOD disorders have less access to appropriate physical health care services--both within the AOD and SMI treatment systems and within health care settings. Recommendations for improved health care for highly stigmatized groups of women with multiple needs include stronger linkages between systems, increased training of health providers, and policy and program changes.

Hair cells without supporting cells: further studies in the ear of the zebrafish mind bomb mutant.

Each sensory hair cell in the ear is normally surrounded by supporting cells, which separate it from the next hair cell. In the mind bomb mutant, as a result of a failure of lateral inhibition, cells that would normally become supporting cells differentiate as hair cells instead, creating sensory patches that consist of hair cells only. This provides a unique opportunity to pinpoint the functions for which supporting cells are required in normal hair cell development. We find that hair cells in the mutant develop an essentially normal cytoskeleton, with a correctly structured hair bundle and well-defined planar polarity, and form apical junctional complexes with one another in standard epithelial fashion. They fail, however, to form a basal lamina or to adhere properly to the adjacent non-sensory epithelial cells, which overgrow them. The hair cells are eventually expelled from the ear epithelium into the underlying mesenchyme, losing their hair bundles in the process. It is not clear whether they undergo apoptosis: many cells staining strongly with the TUNEL procedure are seen but do not appear apoptotic by other criteria. Supporting cells, therefore, are needed to hold hair cells in the otic epithelium and, perhaps, to keep them alive, but are not needed for the construction of normal hair bundles or to give the hair bundles a predictable polarity. Moreover, supporting cells are not absolutely required as a source of materials for otoliths, which, though small and deformed, still develop in their absence.