A case report, focused on vasopressor use and presented in this article, is likely to resonate with many critical care nurses. In this article the authors describe opportunities to enhance safety ...with vasopressor therapy. Specifically, the goal of improving communication among physicians, nurses, and pharmacists around desired endpoints for vasopressor therapy, triggers for reassessment of the therapeutic strategy and cause of the patients shock was identified as an area for improvement. A form piloted within an organization for use during multidisciplinary rounds and key findings is shared. Vasopressors constitute the mainstay of therapy for nearly every hemodynamically unstable patient in critical care. It is hoped that the lessons and information shared help empower critical care nurses to facilitate vasopressor stewardship within their facilities and, ultimately, enhance patient safety.
A case report, focused on vasopressor use and presented in this article, is likely to resonate with many critical care nurses. In this article the authors describe opportunities to enhance safety ...with vasopressor therapy. Specifically, the goal of improving communication among physicians, nurses, and pharmacists around desired endpoints for vasopressor therapy, triggers for reassessment of the therapeutic strategy and cause of the patient's shock was identified as an area for improvement. A form piloted within an organization for use during multidisciplinary rounds and key findings is shared. Vasopressors constitute the mainstay of therapy for nearly every hemodynamically unstable patient in critical care. It is hoped that the lessons and information shared help empower critical care nurses to facilitate vasopressor stewardship within their facilities and, ultimately, enhance patient safety.
Myotonic dystrophy type 1 (DM1) is a dominant genetic disease in which the expansion of long CTG trinucleotides in the 3′ UTR of the myotonic dystrophy protein kinase (DMPK) gene results in toxic RNA ...gain-of-function and gene mis-splicing affecting mainly the muscles, the heart, and the brain. The CUG-expanded transcripts are a suitable target for the development of antisense oligonucleotide (ASO) therapies. Various chemical modifications of the sugar-phosphate backbone have been reported to significantly enhance the affinity of ASOs for RNA and their resistance to nucleases, making it possible to reverse DM1-like symptoms following systemic administration in different transgenic mouse models. However, specific tissue delivery remains to be improved to achieve significant clinical outcomes in humans. Several strategies, including ASO conjugation to cell-penetrating peptides, fatty acids, or monoclonal antibodies, have recently been shown to improve potency in muscle and cardiac tissues in mice. Moreover, intrathecal administration of ASOs may be an advantageous complementary administration route to bypass the blood-brain barrier and correct defects of the central nervous system in DM1. This review describes the evolution of the chemical design of antisense oligonucleotides targeting CUG-expanded mRNAs and how recent advances in the field may be game-changing by forwarding laboratory findings into clinical research and treatments for DM1 and other microsatellite diseases.
Congenital myotonic dystrophy (CDM) is an autosomal dominant multisystemic disorder attributed to a large expansion of CTG trinucleotide repeats within the myotonic dystrophy protein kinase (DMPK) ...gene. In this study, we successfully reprogrammed dermal fibroblasts derived from two pediatric CDM patients and two age-matched individuals into induced pluripotent stem cells (iPSCs) using a non-integrating viral vector. The resulting CDM iPSC lines harbored approximately about 2000 CTG in the mutated DMPK allele. These iPSC lines expressed pluripotency markers and exhibited the capacity to differentiate into cells representing all three germinal layers, confirming their reliability as a research tool for investigating CDM and therapeutic strategies.
Congenital myotonic dystrophy (CDM) is a genetic disease caused by an abnormally long CTG repeat expansion in the DMPK gene, which generally increases in size following intergenerational ...transmission. CDM is the rarest and most severe form of myotonic dystrophy type 1, yet an important number of patient-derived cells are needed to study this heterogeneous disease. Therefore, we have reprogrammed lymphoblastoid cells derived from a 3-year-old male with CDM into induced pluripotent stem cells (iPSCs; CBRCULi015-A) featuring 1800 CTG repeats and characterized their pluripotent state. This cell line constitutes an important resource to study CDM and potential treatments in vitro.
Myotonic dystrophy, or dystrophia myotonica type 1 (DM1), is a multi-systemic disorder and is the most common adult form of muscular dystrophy. It affects not only muscles but also many organs, ...including the brain. Cerebral impairments include cognitive deficits, daytime sleepiness, and loss of visuospatial and memory functions. The expression of mutated transcripts with CUG repeats results in a gain of toxic mRNA function. The antisense oligonucleotide (ASO) strategy to treat DM1 brain deficits is limited by the fact that ASOs do not cross the blood-brain barrier after systemic administration, indicating that other methods of delivery should be considered. ASO technology has emerged as a powerful tool for developing potential new therapies for a wide variety of human diseases, and its potential has been proven in a recent clinical trial. Targeting DMPK mRNA in neural cells derived from human induced pluripotent stem cells obtained from a DM1 patient with the IONIS 486178 ASO abolished CUG-expanded foci, enabled nuclear redistribution of MBNL1/2, and corrected aberrant splicing. Intracerebroventricular injection of the IONIS 486178 ASO in DMSXL mice decreased the levels of mutant DMPK mRNAs by up to 70% throughout different brain regions. It also reversed behavioral abnormalities following neonatal administration. The present study indicated that the IONIS 486178 ASO targets mutant DMPK mRNAs in the brain and strongly supports the feasibility of a therapy for DM1 patients based on the intrathecal injection of an ASO.
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