Defensins are cationic peptides with broad‐spectrum antimicrobial activity. They are members of a supergene family consisting of α and β subtypes and each subtype is comprised of a number of ...different isoforms. For example, human α‐defensin (HAD) has six isoforms, which are expressed by polymorphonuclear leukocytes and Paneth cells. In contrast, human β‐defensin (HBD) has two isoforms that are expressed by epithelial cells of the skin, gut, respiratory and urogenital tracts. Recently, HBD‐1 was detected in human brain biopsy tissue. However, little is known about the expression of HBD‐1 or HBD‐2 in the CNS and whether neural cells can secrete these peptides. For the present study, human astrocyte, microglial, meningeal fibroblast and neuronal cultures were probed for the expression of HBD‐1 and HBD‐2 mRNA and protein. Each cell type was either maintained in tissue culture medium alone or in medium containing lipopolysaccharide (LPS) at concentrations ranging from 0.1 to 1 μg/mL, interleukin‐1 beta (IL‐1β) at 1–50 ng/mL, or tumor necrosis factor alpha (TNF‐α) at the same concentrations. The expression of HBD‐1 and HBD‐2 mRNAs was monitored by RT‐PCR. The cDNA products were sequenced to characterize the gene product. HBD‐2 protein was detected by immunoblot, immunoprecipitation and immunocytochemistry. Results of these studies showed that HBD‐1 mRNA was detected in all cell cultures except in those enriched for neurons. In contrast, HBD‐2 mRNA was detected only in astrocyte cultures that were treated with LPS, IL‐1β or TNF‐α. The detection of the respective proteins correlated positively with the mRNA results. As such, these data represent the first demonstration of HBD‐2 expression by astrocytes and suggest that this peptide may play a role in host defense against bacterial CNS pathogenesis.
Mice homozygous for the viable Sl allele steel-Dickie (Sld) are sterile, severely anemic, and black-eyed white. The nature of the Sldmutation was investigated at the molecular level and was found to ...be due to a 4.0-kilobase intragenic deletion in mast cell growth factor (MGF) genomic sequences, providing conclusive evidence that Sl encodes MGF. As a consequence of this deletion, Sldis only capable of encoding a soluble truncated growth factor that lacks both transmembrane and cytoplasmic domains. Northern analysis indicates that SldmRNA is expressed at approximately wild-type levels in adult tissues, and yeast expression studies suggest that the Sldprotein is as biologically active as wild-type soluble MGF. These studies provide a molecular basis for explaining the Sldphenotype, a description of a germ-line mutation in the transmembrane and cytoplasmic domains of a membrane-bound growth factor, and in vivo evidence for the importance of membrane-bound forms of growth factors in mammalian development.
Previous research has demonstrated both greater difficulty in obtaining follow-up appointments and increased likelihood of return visits to the emergency department (ED) for patients with ...government-funded insurance plans. The purpose of the current study is to determine whether socioeconomic factors, such as race and insurance type, are associated with the frequency of repeat ED visits in pediatric patients with closed fractures.
A review of ED visit data over a 2-year period from a statewide hospital discharge database in New York was conducted. Discharges for patients with a unique person identifier in the database age 17 years and younger were examined for an ICD-9 diagnosis of closed upper or lower extremity fracture. Age, sex, race, and insurance type for patients with a return ED visit within 8 weeks for the same fracture diagnosis were compared with those without a return visit using standard univariate statistical tests and logistic regression analyses.
Of the 68,236 visits reviewed, the revisit rate was 0.85%. Patients of nonwhite or unidentified race were significantly more likely to have a revisit than white patients (OR, 1.27; P=0.006). Patients with government-funded insurance were significantly more likely to have a revisit than those without government-funded insurance (OR, 1.55; P<0.001). Patients with private insurance were significantly less likely to have a revisit than those without private insurance (OR, 0.72; P=0.001).
Our analysis revealed that nonwhite patients are more likely to return to the ED within 8 weeks for the same fracture diagnosis. Patients with government insurance are 55% more likely to have a revisit, whereas patients with private insurance are 28% less likely to have a revisit. Our results suggest that socioeconomic disparities exist in access to orthopaedic care for closed fractures in a pediatric population. Physicians and policy makers should be mindful of these health care disparities when striving to improve access to care among patients and resource utilization in the ED.
Prognostic level II.
The greatest challenge standing in the way of effective in vivo siRNA delivery is creating a delivery vehicle that mediates a high degree of efficacy with a broad therapeutic window. Key ...structure–activity relationships of a poly(amide) polymer conjugate siRNA delivery platform were explored to discover the optimized polymer parameters that yield the highest activity of mRNA knockdown in the liver. At the same time, the poly(amide) backbone of the polymers allowed for the metabolism and clearance of the polymer from the body very quickly, which was established using radiolabeled polymers to demonstrate the time course of biodistribution and excretion from the body. The fast degradation and clearance of the polymers provided for very low toxicity at efficacious doses, and the therapeutic window of this poly(amide)-based siRNA delivery platform was shown to be much broader than a comparable polymer platform. The results of this work illustrate that the poly(amide) platform has a promising future in the development of a siRNA-based drug approved for human use.
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We present follow-up observations with the Sunyaev-Zel'dovich Array (SZA) of optically confirmed galaxy clusters found in the equatorial survey region of the Atacama Cosmology Telescope (ACT): ACT-CL ...J0022-0036, ACT-CL J2051+0057, and ACT-CLJ 2337+0016. ACT-CL J0022-0036 is a newly discovered, massive (Asymptotically = to 10 super(15) M sub(middot in circle)), high-redshift (z = 0.81) cluster revealed by ACT through the Sunyaev-Zel'dovich effect (SZE). Deep, targeted observations with the SZA allow us to probe a broader range of cluster spatial scales, better disentangle cluster decrements from radio point-source emission, and derive more robust integrated SZE flux and mass estimates than we can with ACT data alone. For the two clusters we detect with the SZA we compute integrated SZE signal and derive masses from the SZA data only. ACT-CL J2337+0016, also known as A2631, has archival Chandra data that allow an additional X-ray-based mass estimate. Optical richness is also used to estimate cluster masses and shows good agreement with the SZE and X-ray-based estimates. Based on the point sources detected by the SZA in these three cluster fields and an extrapolation to ACT's frequency, we estimate that point sources could be contaminating the SZE decrement at the lap20% level for some fraction of clusters.
The spatial architecture of the islets of Langerhans is hypothesized to facilitate synchronized insulin secretion among beta cells, yet testing this in vivo in the intact pancreas is challenging. ...Robo betaKO mice, in which the genes Robo1 and Robo2 are deleted selectively in beta cells, provide a unique model of altered islet spatial architecture without loss of beta cell differentiation or islet damage from diabetes. Combining Robo betaKO mice with intravital microscopy, we show here that Robo betaKO islets have reduced synchronized intra-islet Ca.sup.2+ oscillations among beta cells in vivo. We provide evidence that this loss is not due to a beta cell-intrinsic function of Robo, mis-expression or mis-localization of Cx36 gap junctions, or changes in islet vascularization or innervation, suggesting that the islet architecture itself is required for synchronized Ca.sup.2+ oscillations. These results have implications for understanding structure-function relationships in the islets during progression to diabetes as well as engineering islets from stem cells.
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