TOPIC: Because of the link between communication impairments and psychiatric disorders, it is important for nurses and other healthcare professionals to know the warning signs for the need for a ...communication/speech/language evaluation for children during infancy through early childhood.
PURPOSE: This article presents an overview of the role of speech‐language pathologists (SLPs); the expected developmental achievements for youngsters from infancy to age 5 in speech, language, and communication; and the clinically significant warning signs that indicate a need for speech/language assessment.
SOURCES: Sources for this article included published literature on the topic along with the clinical judgment and expertise of the author, a certified SLP.
CONCLUSIONS: Warning signs for referral to an SLP may be subtle and may present in developmental, academic, behavioral, or social–emotional realms. Collaboration between nurses and communication professionals will allow for early identification and intervention. Early detection of speech and language disabilities is key to maximizing the effects of early intervention, resulting in more positive communication outcomes in later life. It has been found that speech and language delays and disorders, with symptoms left untreated, can cause difficulties in learning and socialization that can last into adolescence and beyond. Early identification of children with developmental delay or developmental disabilities may lead to intervention at a young age when chances for improvement may be best.
The retinoblastoma tumour-suppressor protein Rb inhibits cell proliferation by repressing a subset of genes that are controlled by the E2F family of transcription factors and which are involved in ...progression from the G1 to the S phase of the cell cycle. Rb, which is recruited to target promoters by E2F1 (ref. 3), represses transcription by masking the E2F1 transactivation domain and by inhibiting surrounding enhancer elements, an active repression that could be crucial for the proper control of progression through the cell cycle. Some transcriptional regulators act by acetylating or deacetylating the tails protruding from the core histones, thereby modulating the local structure of chromatin: for example, some transcriptional repressors function through the recruitment of histone deacetylases. We show here that the histone deacetylase HDAC1 physically interacts and cooperates with Rb. In HDAC1, the sequence involved is an LXCXE motif, similar to that used by viral transforming proteins to contact Rb. Our results strongly suggest that the Rb/HDAC1 complex is a key element in the control of cell proliferation and differentiation and that it is a likely target for transforming viruses.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract GNE Myopathy is a rare neuromuscular worldwide autosomal recessive disease, which is very common among Persian Jews. The disorder results from mutations in the gene UDP N -Acetylglucosamine ...2-epimerase/ N -Acetylmannosamine kinase (GNE). To date, over 60 different mutations in GNE have been reported to cause the disease worldwide, but a single homozygous mutation, M712T, has been identified in all patients of Persian descent, 10 amino acids before the end of the protein. The same mutation was found in other Jews and non-Jews families in the Middle East therefore we term it the Middle East mutation. The mechanism leading from GNE mutations to the myopathy phenotype is not yet understood. Since the disease is recessive, it most likely results from the lack of wild type GNE protein; therefore the production of wt protein in patients might alleviate the disease phenotype. Trans-splicing is a phenomenon where splicing between two different pre-mRNA molecules occurs. This mechanism can be used to address mutated gene products and correct transcripts defects on the transcript itself, by altering the cis-splicing process but conserving the original endogenous regulation of the gene. Based on an Adeno Associated Virus platform we have generated a series of transplicing vectors designed to transplice the last exon of GNE which carries the most frequent mutation occurring in GNE myopathy. Transfection and infection of these vectors result in transpliced transcripts both in mouse and human cells. Furthermore, human transplicing vectors are able to partially correct the M712T mutation in patients derived muscle cells. The goal of this project is to use an AAV based trans-splicing vector as a gene therapy tool to overcome the GNE myopathy mutation M712T.
In the context of future AAV-based clinical trials for Duchenne myopathy, AAV genome fate in dystrophic muscles is of importance considering the viral capsid immunogenicity that prohibits recurring ...treatments. We followed AAV genome copy numbers after AAV-U7 delivery in the mdx dystrophic mouse. We showed that AAV genomes encoding non-therapeutic U7 were lost from mdx muscles within three weeks after intra-muscular injection. In contrast, AAV genomes encoding U7ex23 restoring expression of a slightly shortened dystrophin were maintained endorsing that the arrest of the dystrophic process is crucial for maintaining viral genomes in transduced fibers. Indeed, muscles treated with low doses of AAV-U7ex23, resulting in sub-optimal exon-skipping, displayed much lower titers of viral genomes, showing that sub-optimal dystrophin restoration does not prevent AAV genome loss. We also followed therapeutic viral genomes in severe dystrophic dKO mice over time after systemic treatment with scAAV9-U7ex23. Dystrophin restoration decreased significantly between 3 and 12 months in various skeletal muscles, which was correlated with important viral genome loss, except in the heart. Altogether these data show that the success of future AAV-U7 therapy for Duchenne patients would require optimal doses of AAV-U7 to induce substantial levels of dystrophin to stabilize the treated fibers and maintain the long lasting effect of the treatment.
Adeno Associated virus serotype 8 (AAV8) is of particular interest as a vector for pre-clinical and clinical trial for Duchenne Muscular Dystrophy (DMD). In several cell lines, this vector has been ...shown to enter cells through clathrin-mediated endocytosis followed by a trafficking through the microtubule network in various endosomal compartments toward the nucleus. To efficiently transduce cells, AAV must undergo multiple levels of regulation in these cellular compartments. In DMD, dystrophin deficiency results in disturbed balance of cellular events i.e., fiber centronucleation, disorganized cytoskeleton, presence of fibrosis. We have recently described a loss of virion genomes from both dogs and mice models of DMD treated with therapeutic molecules vectorized in AAV. Indeed, the pathophysiological state of DMD muscle should impact on virions fate and subsequently affect crucial steps for AAV effectiveness as viral uncoating, viral genome maintenance and consequently, the transduction efficiency of AAV. Our project aims to characterize cellular uptake and intracellular transport of AAV8 in DMD muscular cells, with the goal of optimizing AAV vector use to get the best transduction efficiency with the lowest AAV dose. Our first data showed that AAV8-GFP was less efficient to transduce DMD and control primary muscular cells compared to HeLa cells. Moreover, AAV8 traffics through same endosomal compartment in DMD and control myoblasts, but at different rates during early time points of the transduction. These results suggest that in muscle cells, AAV8 uses different entry and trafficking pathways from those previously described in HeLa cells and that dystrophic cellular status could affect subcellular processing of the vector particles. We will specify the relationship between AAV8 vector entry, trafficking, uncoating, and transduction efficiency in vitro in primary myoblasts/myotubes of DMD patients and controls.
