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Sofft Lindon Pumps 9yevDhfxwS
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FIGURE 5.

SLFN2 controls hematopoietic progenitor colony formation and promotes the growth-suppressive effects of IFNs on primitive hematopoietic precursors. , to test whether the available siRNAs were efficient and selective for the knockdown of SLFN2 in murine cells, NIH3T3 cells were transfected with control siRNAs or siRNAs selectively targeting , and expression of or mRNAs was subsequently examined by real time RT-PCR. Two different pools of SLFN2 siRNA (siRNA1 and siRNA2) and control siRNA (Ctrl siRNA1 and Ctrl siRNA2) were used. The data are presented as percentages of expression in control siRNA transfected cells and represent the means ± S.E. of three experiments. , Sca1+ derived, murine hematopoietic progenitor cells were transfected with control siRNA or -siRNA, and hematopoietic colony progenitor was assessed in clonogenic assays in methylcellulose. Representative plates are shown. . Sca1+ stem cells were isolated from murine bone marrows and plated in methylcellulose in the presence or absence of IFNα ( and ). The cells were either not transfected or were transfected with the control nontargeting siRNAs or SLFN2-targeting siRNAs shown in . Colony formation (colony forming units) of primitive hematopoietic precursors was assessed at day 7 of culture. The data are expressed as percentages of control untransfected cells colony formation and represent means ± S.E. of five () or four () independent experiments. Paired test analysis demonstrated a value of 0.0004 for IFNα-treated Ctrl siRNA1 SLFN2 siRNA1 transfected cells () and a value of 0.007 for IFNα-treated Ctrl siRNA2 SLFN2 siRNA2 transfected cells ().

To further analyze the functional relevance of SLFN2 in cell growth regulation and its role in the generation of IFN responses in other cell types, we generated stable SLFN2 knockdown NIH3T3 cells via expression of shRNA-targeting SLFN2 using the pSIREN Zsgreen retroviral system. SLFN2 expression was selectively knocked down in NIH3T3 cells ( Fig. 6 , A and B ). Cells in which SLFN2 was knocked down exhibited enhanced proliferation compared with their control counterparts ( Fig. 6 C ). IFNα treatment resulted in dose-dependent growth suppression in both NIH3T3 pSIREN Zsgreen Ctrl siRNA and NIH3T3 pSIREN Zsgreen SLFN2-siRNA cells ( Fig. 6 C ). However, in NIH3T3 cells in which SLFN2 was knocked down, IFNα-induced antiproliferative responses were clearly decreased compared with cells expressing SLFN2 ( Fig. 6 C ), indicating that SLFN2 participates in the generation of the growth inhibitory effects of IFNα. On the other hand, SLFN2 knockdown had no effect on IFNα-dependent formation of STAT-containing DNA-binding complexes ( Fig. 6 , D and E ). Similarly, IFNα-dependent Isg15 gene transcription ( Fig. 6 F ) or generation of IFNα-induced antiviral responses ( Fig. 6 G ) were not affected by SLFN2 knockdown. Thus, targeting SLFN2 appears to be impairing IFNα-dependent cell cycle arrest but not IFN-inducible gene transcription or generation of antiviral responses.

The genesis of this literature review was a desire to construct a list of progressive conditions that most would agree are not CP, to assist nonphysician field staff reviewing and abstracting medical and education records in a community setting as part of the Autism and Developmental Disabilities Monitoring Network. This Network is a multisite, collaborative program funded by the Centers for Disease Control and Prevention to monitor the occurrence of developmental disabilities, including CP, in 8-year-old children across the United States. 8 In this exploratory effort, our goal was to identify a list of brain disorders of childhood that by nature of their underlying pathophysiology and prognosis would not meet the nonprogressive component of the definition for CP. In this report, we present the methods for creating our list of progressive brain disorders of childhood and the table of such conditions identified to date.

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As our first goal, we developed criteria for progressive disorders to apply in our literature review ( Table 1 ). Since this activity was focused on a case definition for public health surveillance of CP, in particular for the Autism and Developmental Disabilities Monitoring Network, we concentrated on disorders with progressive features typically occurring by 8 years of age. 8 By definition, we did not consider conditions that are purely myopathies, disorders only involving the spinal cord, or peripheral neuropathies (neuromuscular disorders), since the primary pathology in these conditions is not in the brain. Progressive features were defined primarily by loss of motor skills or milestones, although descriptions of disorders often more broadly described generalized regression, deteriorating clinical courses or neuropathological findings, or normal early development with subsequent developmental delay. If a disorder was clearly a neurodegenerative condition, we decided to list it for the purposes of exclusion from surveillance, even if some of the neurologic findings progressed and others did not. Another important feature that we considered was childhood mortality; lethality alone was not a criterion for progressiveness, since some genetic conditions known for mortality due to malformations or pathophysiologic processes outside of the central nervous system can have static or even improving neurologic manifestations.

Public Health Surveillance Criteria for Progressive Brain Disorders of Childhood

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The criteria took into account what is typical or described in the majority of children with disorders in question. The rationale for this principle was our belief that when neurologic deterioration is a rare feature, typical children with certain diagnoses who might have CP-like features for reasons unrelated to the disorder should not be excluded categorically. In practice, a limitation of applying this principle was the inadequate precision of literature quantifying the occurrence of CP-like features in rare genetic conditions. The issue of the effects of available therapies on natural history also is problematic, including the spectrum of interventions from diet and medications to enzyme replacement and stem-cell transplantation. Unfortunately, with our routine surveillance procedures, without a special study it is typically difficult to ascertain variables such as treatment regimens and timing of therapies that might be important in assessing the adequacy of treatment and its relationship to the clinical outcome of a particular child. 9 For our list of progressive disorders, we did not review the core disorders on the Recommended Uniform Screening Panel for newborns in the United States, 10 since the typical outcome for these conditions has changed because treatment is routinely instituted shortly after birth, thus preventing progressive features, eg, hypotonia and intellectual disability with congenital hypothyroidism. For other conditions with more potential variability in treatment in the general population, we did not consider the effects of such therapies on natural histories, eg, hematopoietic stemcell transplantation in Krabbe disease. The rapid progress expected in the diagnosis and treatment of progressive disorders, with concomitant changes in newborn screening panels as well as clinical practice, is another caveat for the need to continuously update surveillance practices.

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