Clinical telerehabilitation: applications for physiatrists.

Telemedicine offers an innovative approach to increase access to rehabilitation medicine services for patients who live in areas where physiatrists are scarce or absent. This article reviews the current status of telerehabilitation services delivered through real-time videoconferencing to provide support, assessment, and interventions to individuals with impairments or disabilities. A literature review demonstrates various uses of telerehabilitation by physical therapists, occupational therapists, speech and language pathologists, audiologists, recreational therapists, neuropsychologists, nurses, other physician specialists, and physiatrists.

Generation of isogenic pluripotent stem cells differing exclusively at two early onset Parkinson point mutations.

Patient-specific induced pluripotent stem cells (iPSCs) derived from somatic cells provide a unique tool for the study of human disease, as well as a promising source for cell replacement therapies. One crucial limitation has been the inability to perform experiments under genetically defined conditions. This is particularly relevant for late age onset disorders in which in vitro phenotypes are predicted to be subtle and susceptible to significant effects of genetic background variations.

Genetic engineering of human pluripotent cells using TALE nucleases.

Targeted genetic engineering of human pluripotent cells is a prerequisite for exploiting their full potential. Such genetic manipulations can be achieved using site-specific nucleases. Here we engineered transcription activator-like effector nucleases (TALENs) for five distinct genomic loci.

Efficient generation of a biallelic knockout in pigs using zinc-finger nucleases.

Zinc-finger nucleases (ZFNs) are powerful tools for producing gene knockouts (KOs) with high efficiency. Whereas ZFN-mediated gene disruption has been demonstrated in laboratory animals such as mice, rats, and fruit flies, ZFNs have not been used to disrupt an endogenous gene in any large domestic species. Here we used ZFNs to induce a biallelic knockout of the porcine α1,3-galactosyltransferase (GGTA1) gene.

In vivo genome editing restores haemostasis in a mouse model of haemophilia.

Editing of the human genome to correct disease-causing mutations is a promising approach for the treatment of genetic disorders. Genome editing improves on simple gene-replacement strategies by effecting in situ correction of a mutant gene, thus restoring normal gene function under the control of endogenous regulatory elements and reducing risks associated with random insertion into the genome. Gene-specific targeting has historically been limited to mouse embryonic stem cells.

Targeted genome editing across species using ZFNs and TALENs.

Evolutionary studies necessary to dissect diverse biological processes have been limited by the lack of reverse genetic approaches in most organisms with sequenced genomes. We established a broadly applicable strategy using zinc finger nucleases (ZFNs) and transcription activator-like effector nucleases (TALENs) for targeted disruption of endogenous genes and cis-acting regulatory elements in diverged nematode species.

Efficient immunoglobulin gene disruption and targeted replacement in rabbit using zinc finger nucleases.

Rabbits are widely used in biomedical research, yet techniques for their precise genetic modification are lacking. We demonstrate that zinc finger nucleases (ZFNs) introduced into fertilized oocytes can inactivate a chosen gene by mutagenesis and also mediate precise homologous recombination with a DNA gene-targeting vector to achieve the first gene knockout and targeted sequence replacement in rabbits. Two ZFN pairs were designed that target the rabbit immunoglobulin M (IgM) locus within exons 1 and 2.

DNA ligase III promotes alternative nonhomologous end-joining during chromosomal translocation formation.

Nonhomologous end-joining (NHEJ) is the primary DNA repair pathway thought to underlie chromosomal translocations and other genomic rearrangements in somatic cells. The canonical NHEJ pathway, including DNA ligase IV (Lig4), suppresses genomic instability and chromosomal translocations, leading to the notion that a poorly defined, alternative NHEJ (alt-NHEJ) pathway generates these rearrangements. Here, we investigate the DNA ligase requirement of chromosomal translocation formation in mouse cells.

Australian women's perceptions of breast cancer risk factors and the risk of developing breast cancer.

Background: Numerous studies have shown that the majority of women overestimate both their own risk and the populations' risk of developing breast cancer. A number of factors have been found to correlate with perceived risk.

Methods: This paper reports on a telephone survey of a nationally representative sample of approximately 3,000 Australian women aged 30 to 69 years, conducted in 2007, and compares the findings with those of a similar survey conducted in 2003.

Engineering HIV-resistant human CD4+ T cells with CXCR4-specific zinc-finger nucleases.

HIV-1 entry requires the cell surface expression of CD4 and either the CCR5 or CXCR4 coreceptors on host cells. Individuals homozygous for the ccr5Δ32 polymorphism do not express CCR5 and are protected from infection by CCR5-tropic (R5) virus strains. As an approach to inactivating CCR5, we introduced CCR5-specific zinc-finger nucleases into human CD4+ T cells prior to adoptive transfer, but the need to protect cells from virus strains that use CXCR4 (X4) in place of or in addition to CCR5 (R5X4) remains.

Efficient targeted gene disruption in the soma and germ line of the frog Xenopus tropicalis using engineered zinc-finger nucleases.

The frog Xenopus, an important research organism in cell and developmental biology, currently lacks tools for targeted mutagenesis. Here, we address this problem by genome editing with zinc-finger nucleases (ZFNs). ZFNs directed against an eGFP transgene in Xenopus tropicalis induced mutations consistent with nonhomologous end joining at the target site, resulting in mosaic loss of the fluorescence phenotype at high frequencies.

MiRNA-205 modulates cellular invasion and migration via regulating zinc finger E-box binding homeobox 2 expression in esophageal squamous cell carcinoma cells.

Background: Esophageal squamous cell carcinoma (ESCC) is often diagnosed at later stages until they are incurable. MicroRNA (miR) is a small, non-coding RNA that negatively regulates gene expression mainly via translational repression. Accumulating evidence indicates that deregulation of miR is associated with human malignancies including ESCC.

An autocrine TGF-beta/ZEB/miR-200 signaling network regulates establishment and maintenance of epithelial-mesenchymal transition.

Epithelial-mesenchymal transition (EMT) is a form of cellular plasticity that is critical for embryonic development and tumor metastasis. A double-negative feedback loop involving the miR-200 family and ZEB (zinc finger E-box-binding homeobox) transcription factors has been postulated to control the balance between epithelial and mesenchymal states. Here we demonstrate using the epithelial Madin Darby canine kidney cell line model that, although manipulation of the ZEB/miR-200 balance is able to repeatedly switch cells between epithelial and mesenchymal states, the induction and maintenance of a stable mesenchymal phenotype requires the establishment of autocrine transforming growth factor-β (TGF-β) signaling to drive sustained ZEB expression.

The Notch ligand Jagged2 promotes lung adenocarcinoma metastasis through a miR-200-dependent pathway in mice.

Epithelial tumor cells transit to a mesenchymal state in response to extracellular cues, in a process known as epithelial-to-mesenchymal transition (EMT). The precise nature of these cues has not been fully defined, an important issue given that EMT is an early event in tumor metastasis. Here, we have found that a population of metastasis-prone mouse lung adenocarcinoma cells expresses Notch and Notch ligands and that the Notch ligand Jagged2 promotes metastasis.

Education predicts incidence of preclinical mobility disability in initially high-functioning older women. The Women's Health and Aging Study II.

Background: To examine the impact of educational attainment on the incidence of preclinical mobility disability (PCD).

Methods: The Women's Health and Aging II Study is a prospective observational cohort study of 436 initially high-functioning community-dwelling women aged 70-79 years at baseline in Baltimore, Maryland. We measured the association of highest attained education level with preclinical mobility disability (PCD) over an 11-year period.

Dissection of splicing regulation at an endogenous locus by zinc-finger nuclease-mediated gene editing.

Sequences governing RNA splicing are difficult to study in situ due to the great difficulty of traditional targeted mutagenesis. Zinc-finger nuclease (ZFN) technology allows for the rapid and efficient introduction of site-specific mutations into mammalian chromosomes. Using a ZFN pair along with a donor plasmid to manipulate the outcomes of DNA repair, we introduced several discrete, targeted mutations into the fourth intron of the endogenous BAX gene in Chinese hamster ovary cells.

A TALE nuclease architecture for efficient genome editing.

Nucleases that cleave unique genomic sequences in living cells can be used for targeted gene editing and mutagenesis. Here we develop a strategy for generating such reagents based on transcription activator-like effector (TALE) proteins from Xanthomonas. We identify TALE truncation variants that efficiently cleave DNA when linked to the catalytic domain of FokI and use these nucleases to generate discrete edits or small deletions within endogenous human NTF3 and CCR5 genes at efficiencies of up to 25%.

An engineered zinc finger protein activator of the endogenous glial cell line-derived neurotrophic factor gene provides functional neuroprotection in a rat model of Parkinson's disease.

Loss of dopaminergic neurons is primarily responsible for the onset and progression of Parkinson's disease (PD); thus, neuroprotective and/or neuroregenerative strategies remain critical to the treatment of this increasingly prevalent disease. Here we explore a novel approach to neurotrophic factor-based therapy by engineering zinc finger protein transcription factors (ZFP TFs) that activate the expression of the endogenous glial cell line-derived neurotrophic factor (GDNF) gene. We show that GDNF activation can be achieved with exquisite genome-wide specificity.

Enhancing zinc-finger-nuclease activity with improved obligate heterodimeric architectures.

Zinc-finger nucleases (ZFNs) drive efficient genome editing by introducing a double-strand break into the targeted gene. Cleavage is induced when two custom-designed ZFNs heterodimerize upon binding DNA to form a catalytically active nuclease complex. The importance of this dimerization event for subsequent cleavage activity has stimulated efforts to engineer the nuclease interface to prevent undesired homodimerization.

Patient preferences for stroke rehabilitation.

Purpose: Early aggressive rehabilitation therapies maximize functional recovery. We examined patient-reported preferences for their initial rehabilitation therapy setting during their acute stroke hospitalization and whether there was an association between their preferences and their actual discharge destination.

Method: Eligible stroke patients were surveyed during their acute hospital stay at either a primary stroke center or a rural community hospital in North Carolina.

Providing support for the pontic of natural tooth adhesive bridges: a clinical report.

Resin bonded bridges have become established as a treatment option for replacing missing teeth. Their development can be traced to the work of Rochette who used a macro mechanically bonded metal framework to stabilize mobile teeth. Adaptations of Rochette's concept, using natural teeth as pontics, have been presented.

Australian women's awareness of ovarian cancer symptoms, risk and protective factors, and estimates of own risk.

Objective: To examine Australian women's perceived risk of ovarian cancer, reasons for perceived risk levels, and knowledge of ovarian cancer symptoms at two timepoints (2003 and 2007).

Methods: A computer-assisted telephone (CATI) survey of 2,954 Australian women with no history of ovarian cancer was conducted.

Results: Approximately 60% of women perceived their risk of ovarian cancer was similar to other women of their age; 10% indicated an increased risk, and 30% indicated a lower risk.

Osteoporosis treatment following hip fracture: how rates vary by service.

Objectives: Osteoporosis is a prevalent condition among older people. It is often undiagnosed until patients suffer fragility fractures. Previous studies have shown low rates of initiating osteoporosis treatment during the acute hip fracture hospitalization.

Genome editing with engineered zinc finger nucleases.

Reverse genetics in model organisms such as Drosophila melanogaster, Arabidopsis thaliana, zebrafish and rats, efficient genome engineering in human embryonic stem and induced pluripotent stem cells, targeted integration in crop plants, and HIV resistance in immune cells - this broad range of outcomes has resulted from the application of the same core technology: targeted genome cleavage by engineered, sequence-specific zinc finger nucleases followed by gene modification during subsequent repair. Such 'genome editing' is now established in human cells and a number of model organisms, thus opening the door to a range of new experimental and therapeutic possibilities.