Neuronal nitric oxide synthase contributes to the regulation of hematopoiesis

Nitric oxide (NO) signaling is important for the regulation of hematopoiesis. However, the role of individual NO synthase (NOS) isoforms is unclear. Our results indicate that the neuronal NOS isoform (nNOS) regulates hematopolesis in vitro and in vivo. nNOS is expressed in adult bone marrow and fetal liver and is enriched in stromal cells. There is a strong correlation between expression of nNOS in a panel of stromal cell lines established from bone marrow and fetal liver and the ability of these cell lines to support hematopoietic stem cells; furthermore, NO donor can further increase this ability. The number of colonies generated in vitro from the bone marrow and spleen of nNOS-null mutants is increased relative to wild-type or inducible- or endothelial NOS knockout mice. These results describe a new role for nNOS beyond its action in the brain and muscle and suggest a model where nNOS, expressed in stromal cells, produces NO which acts as a paracrine regulator of hematopoietic stem cells

Intranasal “painless” Human Nerve Growth Factors Slows Amyloid Neurodegeneration and Prevents Memory Deficits in App X PS1 Mice

Nerve Growth Factor (NGF) is being considered as a therapeutic candidate for Alzheimer's disease (AD) treatment but the clinical application is hindered by its potent pro-nociceptive activity. Thus, to reduce systemic exposure that would induce pain, in recent clinical studies NGF was administered through an invasive intracerebral gene-therapy approach. Our group demonstrated the feasibility of a non-invasive intranasal delivery of NGF in a mouse model of neurodegeneration. NGF therapeutic window could be further increased if its nociceptive effects could be avoided altogether. In this study we exploit forms of NGF, mutated at residue R100, inspired by the human genetic disease HSAN V (Hereditary Sensory Autonomic Neuropathy Type V), which would allow increasing the dose of NGF without triggering pain. We show that “painless” hNGF displays full neurotrophic and anti-amyloidogenic activities in neuronal cultures, and a reduced nociceptive activity in vivo. When administered intranasally to APPxPS1 mice ( n = 8), hNGFP61S/R100E prevents the progress of neurodegeneration and of behavioral deficits. These results demonstrate the in vivo neuroprotective and anti-amyloidogenic properties of hNGFR100 mutants and provide a rational basis for the development of “painless” hNGF variants as a new generation of therapeutics for neurodegenerative diseases

Peripheral Nervous System Genes Expressed in Central Neurons Induce Growth on Inhibitory Substrates

Trauma to the spinal cord and brain can result in irreparable loss of function. This failure of recovery is in part due to inhibition of axon regeneration by myelin and chondroitin sulfate proteoglycans (CSPGs). Peripheral nervous system (PNS) neurons exhibit increased regenerative ability compared to central nervous system neurons, even in the presence of inhibitory environments. Previously, we identified over a thousand genes differentially expressed in PNS neurons relative to CNS neurons. These genes represent intrinsic differences that may account for the PNS’s enhanced regenerative ability. Cerebellar neurons were transfected with cDNAs for each of these PNS genes to assess their ability to enhance neurite growth on inhibitory (CSPG) or permissive (laminin) substrates. Using high content analysis, we evaluated the phenotypic profile of each neuron to extract meaningful data for over 1100 genes. Several known growth associated proteins potentiated neurite growth on laminin. Most interestingly, novel genes were identified that promoted neurite growth on CSPGs (GPX3, EIF2B5, RBMX). Bioinformatic approaches also uncovered a number of novel gene families that altered neurite growth of CNS neurons

The cyclin-dependent kinase inhibitor p21 (WAF1) is required for survival of differentiating neuroblastoma cells.

We are employing recent advances in the understanding of the cell cycle to study the inverse relationship between proliferation and neuronal differentiation. Nerve growth factor and aphidicolin, an inhibitor of DNA polymerases, synergistically induce neuronal differentiation of SH-SY5Y neuroblastoma cells and the expression of p21WAF1, an inhibitor of cyclin-dependent kinases. The differentiated cells continue to express p21WAF1, even after removal of aphidicolin from the culture medium. The p21WAF1 protein coimmunoprecipitates with cyclin E and inhibits cyclin E-associated protein kinase activity. Each of three antisense oligonucleotides complementary to p21WAF1 mRNA partially blocks expression of p21WAF1 and promotes programmed cell death. These data indicate that p21WAF1 expression is required for survival of these differentiating neuroblastoma cells. Thus, the problem of neuronal differentiation can now be understood in the context of negative regulators of the cell cycle

Interventions for improving community ambulation in individuals with stroke

Background Community ambulation refers to the ability of a person to walk in their own community, outside of their home and also indoors in private or public locations. Some people choose to walk for exercise or leisure and may walk with others as an important aspect of social functioning. Community ambulation is therefore an important skill for stroke survivors living in the community whose walking ability has been affected. Objectives To determine: (1) whether interventions improve community ambulation for stroke survivors, and (2) if any specific intervention method improves community ambulation more than other interventions. Search methods We searched the Cochrane Stroke Group Trials Register (September 2014), the Cochrane Central Register of Controlled Trials (CENTRAL) (November 2013), PubMed (1946 to November 2013), EMBASE (1980 to November 2013), CINAHL (1982 to November 2013), PsycINFO (1887 to November 2013), Scopus (1960 to November 2013), Web of Science (1900 to November 2013), SPORTDiscus (1975 to November 2013), and PEDro, CIRRIE and REHABDATA (November 2013). We also searched ongoing trials registers (November 2013) and reference lists, and performed a cited reference search. Selection criteria Selection criteria included parallel‐group randomised controlled trials (RCTs) and cross‐over RCTs, studies in which participants are adult (aged 18 years or more) stroke survivors, and interventions that were aimed at improving community ambulation. We defined the primary outcome as participation; secondary outcomes included activity level outcomes related to gait and self‐efficacy. Data collection and analysis One review author independently screened titles. Two review authors screened abstracts and full text articles, with a third review author was available to resolve any disagreements. Two review authors extracted data and assessed risk of bias. All outcomes were continuous. The analysis for the primary outcome used the generic inverse variance methods for meta‐analysis, using the standardised mean difference (SMD) and standard error (SE) from the participation outcomes. Analyses for secondary outcomes all used SMD or mean difference (MD). We completed analyses for each outcome with all studies, and by type of community ambulation intervention (community or outdoor ambulation practice, virtual practice, and imagery practice). We considered trials for each outcome to be of low quality due to some trial design considerations, such as who knew what group the participants were in, and the number of people who dropped out of the studies. Main results We included five studies involving 266 participants (136 intervention; 130 control). All participants were adult stroke survivors, living in the community or a care home. Programmes to improve community ambulation consisted of walking practice in a variety of settings and environments in the community, or an indoor activity that mimicked community walking (including virtual reality or mental imagery). Three studies were funded by government agencies, and two had no funding. From two studies of 198 people there was low quality evidence for the effect of intervention on participation compared with control (SMD, 0.08, 95% confidence interval (CI) ‐0.20 to 0.35 (using inverse variance). The CI for the effect of the intervention on gait speed was wide and does not exclude no difference (MD 0.12, 95% CI ‐0.01 to 0.24; four studies, 98 participants, low quality evidence). We considered the quality of the evidence to be low for all the remaining outcomes in our review: Community Walk Test (MD ‐6.35, 95% CI ‐21.59 to 8.88); Walking Ability Questionnaire (MD 0.53, 95% CI ‐5.59 to 6.66); Six‐Minute Walk Test (MD 39.62 metres, 95% CI ‐8.26 to 87.51) and self‐efficacy (SMD 0.32, 95% CI ‐0.09 to 0.72). We downgraded the quality of the evidence because of a high risk of bias and imprecision. Authors' conclusions There is currently insufficient evidence to establish the effect of community ambulation interventions or to support a change in clinical practice. More research is needed to determine if practicing outdoor or community walking will improve participation and community ambulation skills for stroke survivors living in the community

Interventions for improving community ambulation in individuals with stroke

Background Community ambulation refers to the ability of a person to walk in their own community, outside of their home and also indoors in private or public locations. Some people choose to walk for exercise or leisure and may walk with others as an important aspect of social functioning. Community ambulation is therefore an important skill for stroke survivors living in the community whose walking ability has been affected. Objectives To determine: (1) whether interventions improve community ambulation for stroke survivors, and (2) if any specific intervention method improves community ambulation more than other interventions. Search methods We searched the Cochrane Stroke Group Trials Register (September 2014), the Cochrane Central Register of Controlled Trials (CENTRAL) (November 2013), PubMed (1946 to November 2013), EMBASE (1980 to November 2013), CINAHL (1982 to November 2013), PsycINFO (1887 to November 2013), Scopus (1960 to November 2013), Web of Science (1900 to November 2013), SPORTDiscus (1975 to November 2013), and PEDro, CIRRIE and REHABDATA (November 2013). We also searched ongoing trials registers (November 2013) and reference lists, and performed a cited reference search. Selection criteria Selection criteria included parallel‐group randomised controlled trials (RCTs) and cross‐over RCTs, studies in which participants are adult (aged 18 years or more) stroke survivors, and interventions that were aimed at improving community ambulation. We defined the primary outcome as participation; secondary outcomes included activity level outcomes related to gait and self‐efficacy. Data collection and analysis One review author independently screened titles. Two review authors screened abstracts and full text articles, with a third review author was available to resolve any disagreements. Two review authors extracted data and assessed risk of bias. All outcomes were continuous. The analysis for the primary outcome used the generic inverse variance methods for meta‐analysis, using the standardised mean difference (SMD) and standard error (SE) from the participation outcomes. Analyses for secondary outcomes all used SMD or mean difference (MD). We completed analyses for each outcome with all studies, and by type of community ambulation intervention (community or outdoor ambulation practice, virtual practice, and imagery practice). We considered trials for each outcome to be of low quality due to some trial design considerations, such as who knew what group the participants were in, and the number of people who dropped out of the studies. Main results We included five studies involving 266 participants (136 intervention; 130 control). All participants were adult stroke survivors, living in the community or a care home. Programmes to improve community ambulation consisted of walking practice in a variety of settings and environments in the community, or an indoor activity that mimicked community walking (including virtual reality or mental imagery). Three studies were funded by government agencies, and two had no funding. From two studies of 198 people there was low quality evidence for the effect of intervention on participation compared with control (SMD, 0.08, 95% confidence interval (CI) ‐0.20 to 0.35 (using inverse variance). The CI for the effect of the intervention on gait speed was wide and does not exclude no difference (MD 0.12, 95% CI ‐0.01 to 0.24; four studies, 98 participants, low quality evidence). We considered the quality of the evidence to be low for all the remaining outcomes in our review: Community Walk Test (MD ‐6.35, 95% CI ‐21.59 to 8.88); Walking Ability Questionnaire (MD 0.53, 95% CI ‐5.59 to 6.66); Six‐Minute Walk Test (MD 39.62 metres, 95% CI ‐8.26 to 87.51) and self‐efficacy (SMD 0.32, 95% CI ‐0.09 to 0.72). We downgraded the quality of the evidence because of a high risk of bias and imprecision. Authors' conclusions There is currently insufficient evidence to establish the effect of community ambulation interventions or to support a change in clinical practice. More research is needed to determine if practicing outdoor or community walking will improve participation and community ambulation skills for stroke survivors living in the community

Changes in Rural Children’s Use of Time: Evidence from Ethiopia and Andhra Pradesh

In recent decades, children’s time has become a global commodity, fought over by a range of national and international policymakers (Stephens 1995). Ambitious global social policies construct particular visions of childhood and, in doing so, shape how children spend their time. The Millennium Development Goals, the Education For All Dakar Goals, World Bank advocacy for early childhood education, and International Labour Organization campaigns to eliminate child labour, all combine to generate policies that shape children’s lives, changing the way they, their families, and their communities perceive childhood and the appropriate use of children’s time. The content of children’s activities is linked to social values and power relationships within households, institutions, and communities (Morrow and Boyden 2010). In contexts of poverty and other adversities, economic pressures structure children’s time to a considerable degree (and these differ according to children’s gender and whether they live in urban or rural areas). However, the pace of change in developing countries is unprecedented, with somewhat uneven consequences for poverty reduction.</p