Victimization and depression among youth with disabilities in the US child welfare system.

AIM: This study aimed to examine the prevalence of victimization among a United States-wide cohort of youth with disabilities (YWD) investigated for maltreatment in the child welfare system (CWS) and their correlation with mental health. METHODS: Data were drawn from baseline interviews in the second National Survey of Child and Adolescent Well-Being, a national representative survey of youth involved in the CWS. Interviews took place between 2008 and 2009 and included 675 youth, 11-17 years old and residing with biological families across 83 counties nationwide. The sample consisted of 405 females (60.1%) and 270 males (39.9%), mean age = 13.5 years. We identified YWD if they reported one or more physical or neurodevelopmental health condition (n = 247). Reported victimization experiences and Children's Depression Inventory (CDI) scores were analysed using weighted regression analyses. RESULTS: One-quarter of YWD in the CWS reported three or more victimizations during the prior year compared with 19% of youth without disabilities. The odds of YWD reporting a one-unit increase in level of victimization was 75% higher (P < 0.05) than youth without disabilities. Prevalence of clinical depression was significantly higher among YWD (14 vs. 5.5%; P < 0.05). Unlike youth without disabilities, the odds of clinical depression were 92% higher for every one-unit increase in victimization among YWD, controlling for covariates (P < 0.05). Of CWS-involved youth who reported three or more victimizations, 24.4% of YWD and 2.2% of non-disabled youth had CDI scores in the clinical range. CONCLUSION: YWDs in the US CWS are at high risk of experiencing victimization and clinical depression. Our findings suggest that health professionals need to screen CWS-involved YWD for multiple forms of victimization, and develop and implement trauma-informed services that target the mental health sequelae that may jeopardize their independence in adulthood.

SHP-1 regulation of p62(DOK) tyrosine phosphorylation in macrophages.

SHP-1 plays key roles in the modulation of hematopoietic cell signaling. To ascertain the impact of SHP-1 on colony-stimulating factor-1 (CSF-1)-mediated survival and proliferative signaling, we compared the CSF-1 responses of primary bone marrow macrophages (BMM) from wild-type and SHP-1-deficient motheaten (me/me) mice. CSF-1-induced protein tyrosine phosphorylation levels were similar in wild-type and me/me BMM, except for the constitutive hyperphosphorylation of a 62-kDa phosphoprotein (pp62) in me/me macrophages. pp62 was identified as the RASGAP-associated p62(DOK) and was shown to be the major CSF-1R-associated tyrosine-phosphorylated protein in CSF-1-treated BMM. p62(DOK) was found to be constitutively associated with SHP-1 in BMM and in 293T cells, co-expressing p62(dok) and either wild-type or catalytically inert SHP-1 (SHP-1 C453S). In both cell types, the interaction of SHP-1 with p62(DOK) occurred independently of p62(DOK) tyrosine phosphorylation, but only the tyrosine-phosphorylated p62(DOK) was bound by SHP-1 C453S in a far Western analysis. These findings suggest a constitutive association of SHP-1 and p62(DOK) that is either conformation-dependent or indirect as well as a direct, inducible association of the SHP-1 catalytic domain with tyrosine-phosphorylated p62(DOK). p62(DOK) hyperphosphorylation is not associated with altered CSF-1-induced RAS signaling or proliferation. However, whereas wild-type macrophages undergo cell death following CSF-1 removal, me/me macrophages exhibit prolonged survival in the absence of growth factor. Thus, p62(DOK) is a major SHP-1 substrate whose tyrosine phosphorylation correlates with growth factor-independent survival in macrophages.

The major SHP-1-binding, tyrosine-phosphorylated protein in macrophages is a member of the KIR/LIR family and an SHP-1 substrate.

The SH2 domain-containing cytoplasmic protein tyrosine phosphatase, SHP-1, negatively regulates hematopoietic cell signaling. SHP-1 is associated with a tyrosine phosphorylated, plasma membrane-spanning glycoprotein, pp130, in colony stimulating factor-1 stimulated or unstimulated macrophages. This association is phosphotyrosine dependent and is mediated by the amino-terminal SH2 domain of SHP-1. pp130 behaves as a substrate of SHP-1 in vitro and is hyperphosphorylated on tyrosine in SHP-1 deficient macrophages from viable-motheaten mice. Co-immunoprecipitation data indicate that pp130 is the product of the mouse p91/PIR-B gene that encodes a member of the killer cell inhibitory receptor (KIR)/leukocyte immunoglobulin-like receptor (LIR) family. By analogy to the KIRs, p91/PIR-B may represent a novel class of macrophage receptors which act to suppress macrophage activation. These observations identify SHP-1 interactions with and regulation of p91/PIR-B as a potential mechanism for inhibiting the signaling cascades linking extracellular stimuli to macrophage activation and/or development.

Biology and action of colony--stimulating factor-1.

Colony-stimulating factor-1 (CSF-1), also known as macrophage colony-stimulating factor, controls the survival, proliferation, and differentiation of mononuclear phagocytes and regulates cells of the females reproductive tract. It appears to play an autocrine and/or paracrine role in cancers of the ovary, endometrium, breast, and myeloid and lymphoid tissues. Through alternative mRNA splicing and differential post-translational proteolytic processing, CSF-1 can either be secreted into the circulation as a glycoprotein or chondroitin sulfate-containing proteoglycan or be expressed as a membrane-spanning glycoprotein on the surface of CSF-1-producing cells. Studies with the op/op mouse, which possesses an inactivating mutation in the CSF-1 gene, have established the central role of CSF-1 in directly regulating osteoclastogenesis and macrophage production. CSF-1 appears to preferentially regulate the development of macrophages found in tissues undergoing active morphogenesis and/or tissue remodeling. These CSF-1 dependent macrophages may, via putative trophic and/or scavenger functions, regulate characteristics such as dermal thickness, male fertility, and neural processing. Apart from its expression on mononuclear phagocytes and their precursors, CSF-1 receptor (CSF-1R) expression on certain nonmononuclear phagocytic cells in the female reproductive tract and studies in the op/op mouse indicate that CSF-1 plays important roles in female reproduction. Restoration of circulating CSF-1 to op/op mice has preliminarily defined target cell populations that are regulated either humorally or locally by the synthesis of cell-surface CSF-1 or by sequestration of the CSF-1 proteoglycan. The CSF-1R is a tyrosine kinase encoded by the c-fms proto-oncogene product. Studies by several groups have used cells expressing either the murine or human CSF-1R in fibroblasts to pinpoint the requirement of kinase activity and the importance of various receptor tyrosine phosphorylation sites for signaling pathways stimulated by CSF-1. To investigate post-CSF-1R signaling in the macrophage, proteins that are rapidly phosphorylated on tyrosine in response to CSF-1 have been identified, together with proteins associated with them. Studies on several of these proteins, including protein tyrosine phosphates 1C, the c-cbl proto-oncogene product, and protein tyrosine phosphatase-phi are discussed.

The biology and action of colony stimulating factor-1.

Colony stimulating factor 1 (CSF-1) is a growth factor for mononuclear phagocytic cells. Through alternative mRNA splicing and differential post-translational proteolytic processing, CSF-1 can either be secreted into the circulation as a glycoprotein or chondroitin sulfate-containing proteoglycan or expressed as a membrane-spanning glycoprotein on the surface of synthesizing cells. The discovery that the osteopetrotic (op/op) mutant mouse possesses an inactivating mutation in the CSF-1 gene has greatly contributed to our understanding of CSF-1 biology. CSF-1 directly regulates some non-mononuclear phagocytic cells that express the CSF-1 receptor tyrosine kinase, but is not required for their development. However, it directly regulates the development and maintenance of tissue macrophage subpopulations that appear to have important trophic and/or scavenger roles in tissue morphogenesis and function. Depending on the tissue, this regulation may be local (via the cell-surface form) localized (via the sequestered proteoglycan form) or humoral. It appears that the CSF-1 dependent tissue macrophage subpopulations, via their effects on other cell types, can significantly affect functions in tissues as diverse as testis, brain and skin, and their absence in op/op mice may explain the pleiotropy of the op/op phenotype. To investigate post-CSF-1 receptor signaling in the macrophage, procedures have been developed for the purification and sequence determination of the proteins that are rapidly phosphorylated on tyrosine in response to CSF-1. Several have been identified and the behavior of one of them, protein tyrosine phosphatase 1C (PTP1C), is discussed.

Protein tyrosine phosphatase-1C is rapidly phosphorylated in tyrosine in macrophages in response to colony stimulating factor-1.

An approximately 64-kDa cytoplasmic protein is rapidly phosphorylated in tyrosine in the response of macrophages to colony stimulating factor-1. To identify this protein, BAC1.2F5 macrophages were incubated with or without colony stimulating factor-1, the phosphotyrosine-containing portion of their cytosolic fractions subjected to size exclusion chromatography, and the 45-70-kDa fraction further fractionated by reverse phase high pressure liquid chromatography (RP-HPLC). Tryptic peptides of pooled RP-HPLC fractions from stimulated cells (containing the approximately 64-kDa protein and an approximately 54-kDa protein) and from unstimulated cells (containing the approximately 54-kDa protein alone), were sequenced directly. All seven readable sequences of 8 sequenceable peptides present uniquely in the stimulated fraction were present in the sequence of the src homology 2 domain-containing protein tyrosine phosphatase-1C (PTP-1C). The identity of the approximately 64-kDa protein was confirmed by Western blotting with an antibody raised to a PTP-1C peptide. The rapid, growth factor-induced tyrosine phosphorylation of PTP-1C suggests that it may be involved in very early events in growth factor signal transduction.

Tongue-tie (ankyloglossia) and breastfeeding: a review.

Tongue-tie (partial ankyloglossia) is a congenital condition in which the membrane under the tongue is too short or may be attached too near the tip of the tongue, thereby preventing tongue protrusion. Considerable controversy among health professionals persists regarding the appropriate treatment of partial ankyloglossia. Therefore, lactation consultants need to be aware of tongue-tie and its potential negative impact on breastfeeding. This discussion examines issues relating to the possible need for treatment and the role of the lactation consultant in the evaluation and care of the infant who presents with ankyloglossia.

Ribosomal RNA operon anti-termination. Function of leader and spacer region box B-box A sequences and their conservation in diverse micro-organisms.

All Escherichia coli rrn operons show a common motif in which anti-terminator box B-box A sequences occur twice, first in the leader and again in the 16 S-23 S spacer. In this study we have analyzed several aspects of rrn anti-termination by leader and spacer anti-terminator sequences. Using DNA synthesis and a plasmid test system, we incorporated random changes into the leader anti-terminator region and examined these mutations for their ability to read through a strong terminator. We also examined anti-termination by synthetic box A and by rrn spacer region sequences. Information derived from these experiments was used to search the rrn sequences of other micro-organisms for possible anti-termination features. Our principal conclusions were that: (1) box A was sufficient for terminator readthrough; (2) we could show no positive requirement for box B in our test system; (3) many of the negative anti-terminator mutations caused a promoter up-effect in the absence of a terminator; (4) the search of rrn operons from other micro-organisms revealed that anti-terminator-like box B-box A sequences exist in leader and spacer regions of both eubacteria and archaebacteria. The frequent occurrence of this pattern suggested that the E. coli rrn anti-termination motif is widespread in nature and has been conserved in microbial evolution.

Evidence that v-src and v-fps gene products use a protein kinase C-mediated pathway to induce expression of a transformation-related gene.

Induction of the transformation-related gene 9E3 by the v-src and v-fps gene products (v-Src and v-Fps) is blocked in chicken embryo fibroblasts depleted of protein kinase C (PKC). PKC agonists induce 9E3 gene expression. Protein kinase inhibitors block v-Src- and v-Fps-induced 9E3 gene expression with the same dose-response curves seen for PKC agonist-induced 9E3 gene expression. These data suggest that v-Src and v-Fps use a PKC-mediated signal-transduction pathway to induce expression of the transformation-related 9E3 gene. Consistent with this hypothesis, we find that both v-Src and v-Fps rapidly induce phosphorylation of a 67-kDa PKC substrate.

In vivo translation of a region within the rrnB 16S rRNA gene of Escherichia coli.

In this study we show that a segment of the Escherichia coli rrnB 16S gene can be translated in vivo. Other laboratories have previously reported that there are internal transcription and translation signals and open reading frames within the E. coli rrnB rRNA operon. Their studies revealed a translation start signal followed by a 252-base-pair open reading frame (ORF16) within the 16S gene and detected a promoter (p16) in the same general region by using in vitro RNA polymerase binding and transcription initiation assays. By using plasmid gene fusions of ORF16 to lacZ we showed that an ORF16'-'beta-galactosidase fusion protein was made in vivo. Transcripts encoding the fusion protein were expressed either from the rrnB p1p2 control region or from a hybrid trp-lac promoter (tacP), but the amount of expression was considerably less than for a lacZ control plasmid. We used fusions to the cat gene to show that p16 is one-half as active as lacP. Deletions were used to show that p16 is located within ORF16 and thus cannot promote a transcript encoding the ORF16 peptide. A comparison of sequences from different organisms shows that ORF16 and p16 lie in a highly conserved region of the procaryotic 16S RNA structure. The first 20 amino acids of ORF16 are conserved in most eubacterial and plant organellar sequences, and promoter activity has been detected in this region of the Caulobacter crescentus sequence by other workers.

Organization, nucleotide sequence, and transcription of the chicken HSP70 gene.

We have isolated a gene encoding a 70,000-Da heat shock protein (HSP70) from a chicken genomic library. The recombinant clone C411 was isolated by hybridization to a radioactively labeled plasmid containing Drosophila HSP70 gene sequences. The identity was established by hybrid selected translation using a subcloned restriction fragment, pC1.8, and total cytoplasmic RNA from chicken cells. The selected mRNA translated in vitro a product which co-migrates with in vivo synthesized chicken HSP70 by SDS-polyacrylamide gel electrophoresis. By Northern blot analysis of poly(A)+ mRNA from heat-shocked cells, we detected a 2.6-kilobase pair mRNA homologous to pC1.8. The nucleotide sequences within pC1.8 and a flanking 2.0-kilobase pair HindIII fragment contain a single contiguous open reading frame of 1905 nucleotides that corresponds to a protein of predicted size 70,000 daltons. Upstream of the initiator methionine codon, ATG, lie sequences homologous to the canonical transcription elements TATA, CCAAT, and SP1 binding site, and two overlapping heat shock elements. The order and spacing of these sequences share many features in common with the promoter for the human HSP70 gene.