Systematic review of interventions for reducing stigma experienced by children with disabilities and their families in low- and middle-income countries: state of the evidence.

OBJECTIVES: To identify and assess the evidence for interventions to reduce stigma experienced by children with disabilities and their families in low- and middle-income settings. METHODS: Systematic review of seven databases (MEDLINE, EMBASE, Global Health, PsycINFO, Social Policy and Practice, CINAHL, IBSS) for studies of interventions that aimed to reduce stigma for children with disabilities published from January 2000 to April 2018. Data were extracted on study population, study design, intervention level(s) and target group, and type(s) of stigma addressed. A narrative approach was used to synthesise the results. RESULTS: Twenty studies were included. The majority (65%) of interventions targeted enacted stigma (negative attitudes) and the most common intervention approach was education/training (63%). Over half (54%) of interventions were delivered at the organisational/institutional level, and only four studies targeted more than one social level. The most common disability targeted was epilepsy (50%) followed by intellectual impairment (20%). The majority of studies (n = 18/20, 90%) found a reduction in a component of stigma; however, most (90%) studies had a high risk of bias. CONCLUSIONS: This review highlights the lack of quality evidence on effective stigma-reduction strategies for children with disabilities. Validation and consistent use of contextually relevant scales to measure stigma may advance this field of research. Studies that involve people with disabilities in the design and implementation of these strategies are needed.

OBJECTIFS: Identifier et évaluer les données des interventions visant à réduire la stigmatisation subie par les enfants avec des invalidités et leurs familles dans les milieux à revenu faible et intermédiaire. MÉTHODES: Revue systématique de sept bases de données (MEDLINE, EMBASE, Global Health, PsycINFO, Social Policy and Practice, CINAHL, IBSS) pour des études d'interventions visant à réduire la stigmatisation des enfants handicapés publiées de janvier 2000 à avril 2018. Les données ont été extraites sur la population étudiée, la conception de l'étude, le(s) niveau(x) d'intervention et le groupe cible, ainsi que le(s) type(s) de stigmatisation abordé(s). Une approche narrative a été utilisée pour synthétiser les résultats. RÉSULTATS: Vingt études ont été incluses. La majorité (65%) des interventions ciblaient la stigmatisation (attitudes négatives) et l'approche d'intervention la plus courante était l'éducation/la formation (63%). Plus de la moitié (54%) des interventions ont été réalisées au niveau organisationnel/institutionnel et seules quatre études ciblaient plus d'un niveau social. L'invalidité la plus fréquemment ciblée était l'épilepsie (50%) suivie de la déficience intellectuelle (20%). La majorité des études (n = 18/20, 90%) ont trouvé une réduction d'une composante de la stigmatisation, mais la plupart (90%) des études présentaient un risque élevé de biais. CONCLUSIONS: Cette revue met en évidence le manque de données probantes de qualité sur les stratégies efficaces de réduction de la stigmatisation pour les enfants handicapés. La validation et l'utilisation cohérente d'échelles contextuellement pertinentes pour mesurer la stigmatisation pourraient faire avancer ce domaine de recherche. Des études impliquant les personnes avec des invalidités dans la conception et la mise en œuvre de ces stratégies sont nécessaires.

Assessing the social determinants of health care costs for Medicaid-enrolled adolescents in Washington State using administrative data.

OBJECTIVE: The study used administrative data to identify the social determinants that have the greatest impact on Medicaid expenditures in adolescence. DATA SOURCES: Data were compiled using the Washington State Department of Social and Health Services Integrated Client Databases, which link data from state systems including Medicaid claims and social services receipt. STUDY DESIGN: Medical system and behavioral health service costs of over 180 000 Medicaid-enrolled adolescents aged 12-17 were measured using integrated administrative data from Washington State. Social determinants of health, including child maltreatment and parent risk factors, were also measured. Two-stage regression models were used to identify factors associated with increased health care utilization and costs. PRINCIPAL FINDINGS: Regression models revealed that the factors most predictive of higher health care costs were child abuse, child neglect, and instability in out-of-home placements related to foster care. Other social determinants of health, such as parent risk factors, were not associated with health care costs. Child maltreatment and placement instability impacted health care costs primarily through large increases in behavioral health utilization and costs. CONCLUSIONS: Prevention and early interventions for children and families to decrease child maltreatment and increase foster care placement stability could reduce overall health care costs.

Preferential Targeting of Lateral Entorhinal Inputs onto Newly Integrated Granule Cells.

Mature dentate granule cells in the hippocampus receive input from the entorhinal cortex via the perforant path in precisely arranged lamina, with medial entorhinal axons innervating the middle molecular layer and lateral entorhinal cortex axons innervating the outer molecular layer. Although vastly outnumbered by mature granule cells, adult-generated newborn granule cells play a unique role in hippocampal function, which has largely been attributed to their enhanced excitability and plasticity (Schmidt-Hieber et al., 2004; Ge et al., 2007). Inputs from the medial and lateral entorhinal cortex carry different informational content. Thus, the distribution of inputs onto newly integrated granule cells will affect their function in the circuit. Using retroviral labeling in combination with selective optogenetic activation of medial or lateral entorhinal inputs, we examined the functional innervation and synaptic maturation of newly generated dentate granule cells in the mouse hippocampus. Our results indicate that lateral entorhinal inputs provide the majority of functional innervation of newly integrated granule cells at 21 d postmitosis. Despite preferential functional targeting, the dendritic spine density of immature granule cells was similar in the outer and middle molecular layers, which we speculate could reflect an unequal distribution of shaft synapses. However, chronic blockade of neurotransmitter release of medial entorhinal axons with tetanus toxin disrupted normal synapse development of both medial and lateral entorhinal inputs. Our results support a role for preferential lateral perforant path input onto newly generated neurons in mediating pattern separation, but also indicate that medial perforant path input is necessary for normal synaptic development.SIGNIFICANCE STATEMENT The formation of episodic memories involves the integration of contextual and spatial information. Newly integrated neurons in the dentate gyrus of the hippocampus play a critical role in this process, despite constituting only a minor fraction of the total number of granule cells. Here we demonstrate that these neurons preferentially receive information thought to convey the context of an experience. Each newly integrated granule cell plays this unique role for ∼1 month before reaching maturity.

Developmental Sculpting of Intracortical Circuits by MHC Class I H2-Db and H2-Kb.

Synapse pruning is an activity-regulated process needed for proper circuit sculpting in the developing brain. Major histocompatibility class I (MHCI) molecules are regulated by activity, but little is known about their role in the development of connectivity in cortex. Here we show that protein for 2 MHCI molecules H2-Kb and H2-Db is associated with synapses in the visual cortex. Pyramidal neurons in mice lacking H2-Kb and H2-Db (KbDb KO) have more extensive cortical connectivity than normal. Modified rabies virus tracing was used to monitor the extent of pyramidal cell connectivity: Horizontal connectivity is greater in the visual cortex of KbDb KO mice. Basal dendrites of L2/3 pyramids, where many horizontal connections terminate, are more highly branched and have elevated spine density in the KO. Furthermore, the density of axonal boutons is elevated within L2/3 of mutant mice. These increases are accompanied by elevated miniature excitatory postsynaptic current frequency, consistent with an increase in functional synapses. This functional and anatomical increase in intracortical connectivity is also associated with enhanced ocular dominance plasticity that persists into adulthood. Thus, these MHCI proteins regulate sculpting of local cortical circuits and in their absence, the excess connectivity can function as a substrate for cortical plasticity throughout life.

Blocking PirB up-regulates spines and functional synapses to unlock visual cortical plasticity and facilitate recovery from amblyopia.

During critical periods of development, the brain easily changes in response to environmental stimuli, but this neural plasticity declines by adulthood. By acutely disrupting paired immunoglobulin-like receptor B (PirB) function at specific ages, we show that PirB actively represses neural plasticity throughout life. We disrupted PirB function either by genetically introducing a conditional PirB allele into mice or by minipump infusion of a soluble PirB ectodomain (sPirB) into mouse visual cortex. We found that neural plasticity, as measured by depriving mice of vision in one eye and testing ocular dominance, was enhanced by this treatment both during the critical period and when PirB function was disrupted in adulthood. Acute blockade of PirB triggered the formation of new functional synapses, as indicated by increases in miniature excitatory postsynaptic current (mEPSC) frequency and spine density on dendrites of layer 5 pyramidal neurons. In addition, recovery from amblyopia--the decline in visual acuity and spine density resulting from long-term monocular deprivation--was possible after a 1-week infusion of sPirB after the deprivation period. Thus, neural plasticity in adult visual cortex is actively repressed and can be enhanced by blocking PirB function.

Synapse elimination and learning rules co-regulated by MHC class I H2-Db.

The formation of precise connections between retina and lateral geniculate nucleus (LGN) involves the activity-dependent elimination of some synapses, with strengthening and retention of others. Here we show that the major histocompatibility complex (MHC) class I molecule H2-D(b) is necessary and sufficient for synapse elimination in the retinogeniculate system. In mice lacking both H2-K(b) and H2-D(b) (K(b)D(b)(-/-)), despite intact retinal activity and basal synaptic transmission, the developmentally regulated decrease in functional convergence of retinal ganglion cell synaptic inputs to LGN neurons fails and eye-specific layers do not form. Neuronal expression of just H2-D(b) in K(b)D(b)(-/-) mice rescues both synapse elimination and eye-specific segregation despite a compromised immune system. When patterns of stimulation mimicking endogenous retinal waves are used to probe synaptic learning rules at retinogeniculate synapses, long-term potentiation (LTP) is intact but long-term depression (LTD) is impaired in K(b)D(b)(-/-) mice. This change is due to an increase in Ca(2+)-permeable AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors. Restoring H2-D(b) to K(b)D(b)(-/-) neurons renders AMPA receptors Ca(2+) impermeable and rescues LTD. These observations reveal an MHC-class-I-mediated link between developmental synapse pruning and balanced synaptic learning rules enabling both LTD and LTP, and demonstrate a direct requirement for H2-D(b) in functional and structural synapse pruning in CNS neurons.

Neuroprotection from stroke in the absence of MHCI or PirB.

Recovery from stroke engages mechanisms of neural plasticity. Here we examine a role for MHC class I (MHCI) H2-Kb and H2-Db, as well as PirB receptor. These molecules restrict synaptic plasticity and motor learning in the healthy brain. Stroke elevates neuronal expression not only of H2-Kb and H2-Db, but also of PirB and downstream signaling. KbDb knockout (KO) or PirB KO mice have smaller infarcts and enhanced motor recovery. KO hippocampal organotypic slices, which lack an intact peripheral immune response, have less cell death after in vitro ischemia. In PirB KO mice, corticospinal projections from the motor cortex are enhanced, and the reactive astrocytic response is dampened after MCAO. Thus, molecules that function in the immune system act not only to limit synaptic plasticity in healthy neurons, but also to exacerbate brain injury after ischemia. These results suggest therapies for stroke by targeting MHCI and PirB.

CD8+ T cells directed against a viral peptide contribute to loss of motor function by disrupting axonal transport in a viral model of fulminant demyelination.

Demyelination, a pathological hallmark of multiple sclerosis, may be a necessary but not a sufficient condition for motor dysfunction associated with this disease. We favor a neurodegenerative model of multiple sclerosis and suggest that demyelination creates a permissive environment wherein the denuded axon becomes susceptible to immune-mediated injury. Unfortunately, the cellular effectors responsible for eliciting such axonal injury are currently unknown. Based on previous observations implicating cytotoxic T cells in this injury, we assessed motor function, axon dropout, and axon injury following peptide depletion of the immunodominant CD8+ antiviral T cell response in the IFNgamma receptor-deficient mouse model of acute demyelination. We found that the targeted removal of this population of cytotoxic effector cells prior to infection with the Theiler's murine encephalomyelitis virus caused a substantial preservation of motor function at 45 days postinfection that was associated with preservation of retrograde axonal transport in a subpopulation of surviving axons within the spinal cord. We conclude that cytotoxic T cells may be responsible for the initiation of axon injury following demyelination.

Short days increase hypothalamic-pituitary-adrenal axis responsiveness.

Individuals dramatically alter physiology and behavior to adapt to seasonal changes in their environment. To cope with winter stressors such as reduced food availability and low temperatures, central stress responses are presumably modulated at the level of the hypothalamic-pituitary-adrenal (HPA) axis, but the details remain unspecified. We examined the effects of long or short photoperiods (day lengths) on corticosterone responses to restraint, HPA negative feedback sensitivity, glucocorticoid receptor gene expression in the hippocampus, the role of corticosterone in spatial learning, and corticosterone responses to stressors associated with the spatial water maze task in adult male white-footed mice (Peromyscus leucopus). Short days increased corticosterone responses to restraint, increased hippocampal glucocorticoid receptor expression, enhanced corticosterone negative feedback on the HPA axis, and increased sensitivity to dexamethasone suppression of corticosterone. Although spatial learning and memory performance (via water maze) of all mice was impaired after pharmacological corticosterone inhibition, both water maze exposure and treatment injections alone were sufficient to increase short-day, but not long-day, corticosterone concentrations. Thus, the effects of corticosterone on spatial learning in these mice may be complicated by photoperiodic differences in stressor response to the learning task itself. Overall, these results suggest that photoperiod-evoked modification of the HPA axis and its potential behavioral consequences may be adaptive for winter survival.

Absence of perforin expression confers axonal protection despite demyelination.

Current evidence suggests that demyelination may be a necessary but not a sufficient condition for neurologic deficits associated with multiple sclerosis. Axon injury that occurs within the permissive environment of the demyelinated lesion is better correlated with functional deficits, but the mechanisms and cellular effectors of this injury are largely unknown. In an effort to identify potential axon injury mediators, we examined demyelination, motor function, and the number of spinal axons in perforin-deficient mice. Perforin is a critical molecular mediator of cytotoxic immunological injury and we hypothesized that genetic deletion of perforin expression would protect demyelinated axons. Indeed, we found that while perforin-deficient mice had considerable spinal cord demyelination 180 days after infection with Theiler's murine encephalomyelitis virus, such mice exhibited functional and axonal preservation comparable to non-demyelinated perforin-competent controls. We conclude that perforin-dependent effector cells such as cytotoxic T cells, gammadelta T cells, and natural killer cells may play a role in axon damage that is dependent upon but separable from demyelination.