Treatment of a mouse model of spinal cord injury by transplantation of human induced pluripotent stem cell-derived long-term self-renewing neuroepithelial-like stem cells

Because of their ability to self-renew, to differentiate into multiple lineages, and to migrate toward a damaged site, neural stem cells (NSCs), which can be derived from various sources such as fetal tissues and embryonic stem cells, are currently considered to be promising components of cell replacement strategies aimed at treating injuries of the central nervous system, including the spinal cord. Despite their efficiency in promoting functional recovery, these NSCs are not homogeneous and possess variable characteristics depending on their derivation protocols. The advent of induced pluripotent stem (iPS) cells has provided new prospects for regenerative medicine. We used a recently developed robust and stable protocol for the generation of long-term, self-renewing, neuroepithelial-like stem cells from human iPS cells (hiPS-lt-NES cells), which can provide a homogeneous and well-defined population of NSCs for standardized analysis. Here, we show that transplanted hiPS-lt-NES cells differentiate into neural lineages in the mouse model of spinal cord injury (SCI) and promote functional recovery of hind limb motor function. Furthermore, using two different neuronal tracers and ablation of the transplanted cells, we revealed that transplanted hiPS-lt-NES cell-derived neurons, together with the surviving endogenous neurons, contributed to restored motor function. Both types of neurons reconstructed the corticospinal tract by forming synaptic connections and integrating neuronal circuits. Our findings indicate that hiPS-lt-NES transplantation represents a promising avenue for effective cell-based treatment of SCI.     

Ultrastructural changes in cerebral capillary pericytes in aged Notch3 mutant transgenic mice

Pericytes, the specialized vascular smooth muscle cells (VSMCs), play an important role in supporting and maintaining the structure of capillaries. Pericytes show biochemical and physiologic features similar to VSMC, usually containing smooth muscle actin fibers and rich endoplasm reticulum. Studies have indicated that degeneration of VSMCs due to Notch3 mutations is the cause of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). However, it remains unclear whether the Notch3 mutation also affects cerebral cortex capillary pericytes. In this ultrastructural morphologic study, the authors have observed pathological changes in the cerebral cortex capillary pericytes in aged mice that carry human mutant Notch3 genes. The number of abnormal pericytes in the cerebral cortex in Notch3 gene mutant mice was slightly increased when compared to an age-matched control group. Morphologically, the pericytes in the brains of Notch3 gene mutant mice showed more severe cellular injury, such as the presence of damaged mitochondria, secondary lysosomes, and large cytoplasmic vesicles. In addition, morphologic structures related to autophagy were also present in the pericytes of Notch3 gene mutant group. These ultrastructural morphologic alterations suggest that Notch3 mutation precipitates age-related pericytic degeneration that might result in cellular injury and trigger autophagic apoptosis. Microvascular dysfunction due to pericyte degeneration could initiate secondary neurodegenerative changes in brain parenchyma. These findings provide new insight into understanding the role of pericyte degeneration in the phathogenesis of CADASIL disease.     

A new synthetic TLR4 agonist, GLA, allows dendritic cells targeted with antigen to elicit Th1 T-cell immunity in vivo

Protein‐based vaccines offer safety and cost advantages but require adjuvants to induce immunity. Here we examined the adjuvant capacity of glucopyranosyl lipid A (GLA), a new synthetic non‐toxic analogue of lipopolysaccharide. In mice, in comparison with non‐formulated LPS and monophosphoryl lipid A, formulated GLA induced higher antibody titers and generated Type 1 T‐cell responses to HIV gag‐p24 protein in spleen and lymph nodes, which was dependent on TLR4 expression. Immunization was greatly improved by targeting HIV gag p24 to DCs with an antibody to DEC‐205, a DC receptor for antigen uptake and processing. Subcutaneous immunization induced antigen‐specific T‐cell responses in the intestinal lamina propria. Immunity did not develop in mice transiently depleted of DCs. To understand how GLA works, we studied DCs directly from vaccinated mice. Within 4 h, GLA caused DCs to upregulate CD86 and CD40 and produce cytokines including IL‐12p70 in vivo. Importantly, DCs removed from mice 4 h after vaccination became immunogenic, capable of inducing T‐cell immunity upon injection into naïve mice. These data indicate that a synthetic and clinically feasible TLR4 agonist rapidly stimulates full maturation of DCs in vivo, allowing for adaptive immunity to develop many weeks to months later.     

S100A9 a new marker for monocytic human myeloid-derived suppressor cells

Myeloid-derived suppressor cells (MDSC) are a heterogeneous population of cells that negatively regulate the immune response during tumour progression, inflammation and infection. Only limited data are available on human MDSC because of the lack of specific markers. We have identified members of the S100 protein family-S100A8, S100A9 and S100A12 - specifically expressed in CD14(+) HLA-DR(-/low) MDSC. S100A9 staining in combination with anti-CD14 could be used to identify MDSC in whole blood from patients with colon cancer. An increase in the population of CD14(+) S100A9(high) MDSC was observed in the peripheral blood from colon cancer patients in comparison with healthy controls. Finally, nitric oxide synthase expression, a hallmark of MDSC, was induced in CD14(+) S100A9(high) upon lipopolysaccharide/interferon-γ stimulation. We propose S100 proteins as useful markers for the analysis and further characterization of human MDSC.     

Screening high school students for eating disorders: validity of brief behavioral and attitudinal measures

BACKGROUND: Early identification can greatly impact the trajectory of eating disorders, and school‐based screening is 1 avenue for identifying those at risk. To be feasible in a school setting, a screening program must use a brief, valid screening tool. The aim of this study was to assess how well brief attitudinal and behavioral survey items identify adolescents at risk in a large sample of high school students from across the United States. METHODS: Data were drawn from the National Eating Disorder Screening Program, the first‐ever national eating disorders screening initiative for US high schools. A 2‐stage, clustered sampling method was used to randomly select a subset of student screening forms (n = 5740), which included the Eating Attitudes Test (EAT‐26), behavioral questions assessing the frequency of vomiting and binge eating in the past 3 months, and an attitudinal item that assessed preoccupation with thinness. RESULTS: Nearly 12% of females and 3% of males reported vomiting to control their weight and 17% of females and 10% of males reported binge eating 1 or more times per month. Approximately 24% of females and 8% of males report being preoccupied with being thinner. We found that the attitudinal measure yielded high sensitivity and specificity. Combined screening measures that used both the attitudinal and behavioral items yielded slightly higher sensitivity values than those found with the attitudinal measure alone. CONCLUSION: High school administrators should include items that assess both preoccupation with thinness as well as behavioral items that deal with eating disorders on student health surveys.     

The blind spot in the drive for childhood obesity prevention: bringing eating disorders prevention into focus as a public health priority

Public health attention to childhood obesity has increased in tandem with the growing epidemic, but despite this intense focus, successes in prevention have lagged far behind. There is a blind spot in our drive for childhood obesity prevention that prevents us from generating sufficiently broad solutions. Eating disorders and the constellation of perilous weight-control behaviors are in that blind spot. Evidence is mounting that obesity and eating disorders are linked in myriad ways, but entrenched myths about eating disorders undermine our ability to see the full range of leverage points to target in obesity preventive intervention studies. Our efforts to prevent childhood obesity can no longer afford to ignore eating disorders and the assemblage of related behaviors that persist unabated.