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.

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.

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.

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.

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.

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.

Treatment for mental illness and substance abuse in a public psychiatric hospital. Successful strategies and challenging problems.

Although the literature on dual diagnosis has grown considerably over the last several years, report describing inpatient treatment models are less common. We describe some of the major treatment concerns in the dural diagnosis literature, such as using 12-step self-help programs like Alcoholics Anonymous (AA) or Narcotics Anonymous (NA), dealing with different stages of treatment, and developing a program with integrated substance abuse and psychiatric treatment. The practical application of these treatment issues is featured by showing how they are incorporated into an innovative inpatient dual diagnosis treatment program at a public psychiatric hospital. Finally, the treatment program is described in detail regarding administrative issues, staff training, daily treatment schedules, and patient demographics.

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.

Characteristics of participants in a supported education program for adults with psychiatric disabilities.

OBJECTIVE: Supported education programs provide assistance, preparation, and support to individuals with psychiatric disabilities who desire to pursue postsecondary education. To determine the extent to which "typical" clients with severe mental illness can participate in a supported education program, the study examined characteristics of participants in a large supported education program. METHODS: Baseline interviews with participants in a supported education program in the metropolitan Detroit area gathered demographic data, as well as information about school, work, and psychiatric history; social adjustment and support; psychiatric symptoms; and self-perceptions in the areas of school efficacy and self-esteem. Cluster analysis used five variables (sex, age, educational attainment, work background, and symptoms) to produce a client typology. RESULTS: Five clusters emerged: well-functioning young men, young aspiring women, young dependent men, well-functioning but unemployed participants, and distressed unemployed participants. The clusters also differed on a large number of variables not used in the cluster analysis. However, members of all clusters had similar rates of program participation and first-semester attendance. Overall, the supported education participants were younger, better educated, and higher functioning than subjects in general samples of persons with severe mental illness. Although many participants had significant problems with symptoms, social adjustment, and substance abuse, they were able to remain active program participants. CONCLUSIONS: The results indicate that supported education is a feasible alternative for many individuals to meet goals for educational advancement, personal development, and better jobs.

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.

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.

Consumers as mental health providers: first-person accounts of benefits and limitations.

Community support programs are increasingly establishing paid service positions designated exclusively for consumers. Project WINS (Work Incentives and Needs Study), a hybrid case management-vocational program for individuals with severe mental illness, used consumers as peer support specialists (PSSs) to supplement professional roles. Semistructured interviews were conducted with PSSs about 12 months after their employment ended. They identified substantial personal benefits specific to consumer-designated roles (e.g., a "safe" employment setting with accommodations) and general benefits from employment. Problems described were just as numerous, encompassing attitudes toward assigned peers and costs to their own well-being. Critical commentary addressed program operations (structure, supervision, and training needs) and problems in the mental health system. The authors discuss the changed sense of self that service provider roles can create for consumers and suggest that mental health administrators provide anticipatory socialization for this service innovation throughout their agencies and ongoing supports for consumers in their new roles.

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.

An analysis of allegations of sexual abuse in a multi-victim day-care center case.

Sexual abuse in day-care centers is a phenomenon of increasing concern, both in terms of its prevalence and its serious effects on child victims. Legal intervention in this area is problematic because criminal investigations are usually beset with difficulties: Characteristics of children and of the abuse situation affect disclosure rates and credibility. Research on children as witnesses is amassing; however, so far, little systematic analysis has been conducted on multi-victim child sexual abuse cases. The present study concerns a case of sexual abuse in a day-care center with over 100 alleged victims. Criteria derived from Statement Validity Analysis (SVA) protocols were applied to aggregate record review data to assess the veritability of the abuse allegations. Individual children's abuse disclosures were also analyzed, vis-à-vis characteristics of the children (age, gender, recency of attendance) and of the investigation (agency doing the interview, number of interviews, use of anatomically detailed dolls). The use of SVA criteria supported the veritability of allegations in this day-care abuse case. Even acknowledging the limitations of archival data collected for other purposes, the aggregate data analysis reflected consistency, logical structure, and spontaneity; however, little evidence of accommodation was found. Multivariate comparison of disclosing and nondisclosing children found an unexpected inverse relationship of disclosure with age, as well as positive associations with number of interviews and use of dolls. Alternative interpretations of these results are discussed.

Motherhood for women with serious mental illness: pregnancy, childbirth, and the postpartum period.

Although women with serious mental illness have normal fertility rates, the literature points to multiple risk factors and a paucity of emotional and economic support during the initial phases of parenthood. Since most research has focused on child outcomes, the extent and nature of parenting problems experienced by these mothers are not adequately understood. An emphasis on the context of parenting and the meaning of pregnancy and childbearing to these mothers is called for and implications for research and clinical practice 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.

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.

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.

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.

Shedding light on elder abuse.

Elder abuse as a social problem has become the focus of nursing research only in the past decade. As information about the incidence and prevalence of spousal and child abuse came to light, data emerged regarding dependent elderly being abused by adult caregivers, often their children. Documenting and defining elder abuse has been problematic because of a lack of consensual definition and the social stigma surrounding the problem. Standardized assessment methods are still lacking. Nursing research studies focusing on abuse have begun to clarify the variables of abuse and have helped to describe potentially abusive family caregivers. These studies have laid the groundwork for generating theory that will be useful to practitioners to identify and intervene in this family violence arena.