Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder caused by an abnormal expansion of CAG repeats. Although pathogenesis has been attributed to this polyglutamine expansion, the underlying mechanisms through which the huntingtin protein functions have yet to be elucidated. It has been suggested that postnatal reduction of mutant huntingtin through protein interference or conditional gene knockout could prove to be an effective therapy for patients suffering from HD. For allele-specific targeting, transcription activator-like effectors (TALE) were designed to target single-nucleotide polymorphisms (SNP) in the mutant allele and packaged into a vector backbone containing KRAB to promote transcriptional repression of the disease-associated allele. Additional TALEs were packaged into a vector backbone containing heterodimeric FokI and were designed to be used as nucleases (TALEN) to cause a CAG-collapse in the mutant allele. Human HD fibroblasts were treated with each TALE-SNP or TALEN. Allele-expression was measured using a SNP-genotyping assay and mutant protein aggregation was quantified with Western blots for anti-ubiquitin. The TALE-SNP and TALEN significantly reduced mutant allele expression (p < 0.05) when compared to control transfections while not affecting expression of the nondisease allele. This study demonstrates the potential of allele-specific gene modification using TALE proteins, and provides a foundation for targeted treatment for individuals suffering from Huntington’s or other genetically linked diseases.

Pericyte loss or migration from its vascular location may be an important step in microvascular remodeling. Decreased pericyte to endothelial ratios are characteristics of newly formed vessels as well as microvessels undergoing regression, and may be due to selective degeneration via necrotic cell death or via programmed cell death. In this study, we have examined glucocorticoid-induced apoptosis in primary rat CNS pericytes. Characterization of apoptosis was determined using five independent criteria: (1) the translocation of receptors for annexin V from the inner to the outer surface of the plasma membrane, (2) the translocation of cytochrome C from the mitochondria to the cytosol, (3) the induction of DNA fragmentation, (4) the induction of classic changes in cell morphology, and (5) the appearance of TUNEL-positive cells. Incubation of CNS pericytes with dexamethasone induced the appearance of apoptotic cells in a time- and dose-dependent manner. Pericytes express immunologically detectable glucocorticoid receptors, and addition of the glucocorticoid receptor antagonist mifepristone inhibited dexamethasone-induced pericyte apoptosis. That pericytes undergo apoptosis in response to dexamethasone suggests that the regulatory function of this steroid may be important in vascular development and that pericyte apoptotic cell death may accompany vascular regression. Deregulation of pericyte involvement in vascular homeostasis and hemostasis may result in clinical disease.

Study objective Approximately 5% of emergency department patients present with altered mental status (AMS). AMS is diagnostically challenging because of the wide range of causes and is associated with high mortality. We sought to develop a clinical decision rule predicting admission risk among emergency department (ED) patients with AMS. Methods Using retrospective chart review of ED encounters for AMS over a 2‐month period, we recorded causes of AMS and numerous clinical variables. Encounters were split into those admitted to the hospital (“cases”) and those discharged from the ED (“controls”). Using the first month's data, variables correlated with hospital admission were identified and narrowed using univariate and multivariate statistics, including recursive partitioning. These variables were then organized into a clinical decision rule and validated on the second month's data. The decision rule results were also compared to 1‐year mortality. Results We identified 351 encounters for AMS over a 2‐month period. Significant contributors to AMS included intoxication and chronic disorder decompensation. ED data predicting hospital admission included vital sign abnormalities, select lab studies, and psychiatric/intoxicant history. The decision rule sorted patients into low, moderate, or high risk of admission (11.1%, 44.3%, and 89.1% admitted, respectively) and was predictive of 1‐year mortality (low‐risk group 1.8%, high‐risk group 34.3%). Conclusions We catalogued common causes for AMS among patients presenting to the ED, and our data‐driven decision tool triaged these patients for risk of admission with good predictive accuracy. These methods for creating clinical decision rules might be further studied and improved to optimize ED patient care.

Huntington’s Disease (HD) is a neurodegenerative disorder caused by the expansion of CAG repeats on exon 1 of the huntingtin (htt) gene. This mutation results in the expression of an aberrant protein, mutant HTT, which sets in place a cascade of events that eventually leads to neuronal death within the basal ganglia and cerebral cortex. MicroRNAs (miRNAs) are a class of small non-coding RNAs of 18 - 22 nucleotides long that play important roles in post-transcriptional regulation due to their abilities to interact with the 3'-UTR regions of mRNAs. Though generated in the nucleus, a significant portion of miRNAs are secreted into the plasma as free molecules or in vesicles for intercellular signaling. Those circulating miRNAs may provide a unique opportunity to study important pathophysiological mechanisms in HD in a non-invasive manner due to their resistance to degradation, ease of detection, and their known regulatory roles in response to inflammation and neurodevelopmental disorders. More recent studies have suggested that miRNA could be used in therapeutic applications. In this study, we sought to identify the aberrant expression of specific miRNAs extracted from the plasma of early-stage HD patients. Clinical Trial Registration number: NCT01937923

nerve receptors 4 and molecular mimicry between the virus and the human heat shock proteins 90 and 60 5 was incriminated in post-COVID-19 GBS.As no data exist for COVID-19 vaccine, we found 2 possible mechanisms involved in postinfluenza vaccine GBS: the synergistic effects of endotoxin and vaccine-induced autoimmunity. 6 A genetic susceptibility such as certain major histocompatibility complex alleles predisposes individuals to autoimmunity. 7 Other immune secondary effects were reported after AstraZeneca vaccination such as immune thrombocytopenia mediated by platelet-activating antibodies 2 or transverse myelitis found in 2 patients in the clinical trial. 8 For a fuller understanding of the causes of GBS and its possible relationship with the novel COVID-19 vaccines, additional research is required.However, the relative small incidence of postvaccine GBS and the reduction of the severe acute respiratory syndrome coronavirus 2 infection rate in the vaccinated population suggest that the vaccination benefits outweigh the risks.