The origin of human chromosome 2 analyzed by comparative chromosome mapping with a DNA microlibrary

Fluorescencein situ hybridization (FISH) of microlibraries established from distinct chromosome subregions can test the evolutionary conservation of chromosome bands as well as chromosomal rearrangements that occurred during primate evolution and will help to clarify phylogenetic relationships. We used a DNA library established by microdissection and microcloning from the entire long arm of human chromosome 2 for fluorescencein situ hybridization and comparative mapping of the chromosomes of human, great apes (Pan troglodytes, Pan paniscus, Gorilla gorilla, Pongo pygmaeus) and Old World monkeys (Macaca fuscata andCercopithecus aethiops). Inversions were found in the pericentric region of the primate chromosome 2p homologs in great apes, and the hybridization pattern demonstrates the known phylogenetically derived telomere fusion in the line that leads to human chromosome 2. The hybridization of the 2q microlibrary to chromosomes of Old World monkeys gave a different pattern from that in the gorilla and the orang-utan, but a pattern similar to that of chimpanzees. This suggests convergence of chromosomal rearrangements in different phylogenetic lines

Unstable TTTTA/TTTCA expansions in MARCH6 are associated with Familial Adult Myoclonic Epilepsy type 3

Familial Adult Myoclonic Epilepsy (FAME) is a genetically heterogeneous disorder characterized by cortical tremor and seizures. Intronic TTTTA/TTTCA repeat expansions in SAMD12 (FAME1) are the main cause of FAME in Asia. Using genome sequencing and repeat-primed PCR, we identify another site of this repeat expansion, in MARCH6 (FAME3) in four European families. Analysis of single DNA molecules with nanopore sequencing and molecular combing show that expansions range from 3.3 to 14 kb on average. However, we observe considerable variability in expansion length and structure, supporting the existence of multiple expansion configurations in blood cells and fibroblasts of the same individual. Moreover, the largest expansions are associated with micro-rearrangements occurring near the expansion in 20% of cells. This study provides further evidence that FAME is caused by intronic TTTTA/TTTCA expansions in distinct genes and reveals that expansions exhibit an unexpectedly high somatic instability that can ultimately result in genomic rearrangements

Pleth Variability Index to Assess Course of Illness in Children with Asthma

© 2018 Elsevier Inc. Background: Status asthmaticus (SA) is a common reason for admission to the pediatric emergency department (ED). Assessing asthma severity efficiently in the ED can be challenging for clinicians. Adjunctive tools for the clinician have demonstrated inconsistent results. Studies have shown that pulsus paradoxus (PP) correlates with asthma severity. Pleth Variability Index (PVI) is a surrogate measure of PP. Objective: We investigated whether PVI at triage correlates with disposition from the ED. Methods: We recruited children aged 2–18 years old who presented to the pediatric ED of a tertiary care children\u27s hospital with SA. PVI, Respiratory Severity Score, and vital signs were documented at triage and 2 hours into each patient\u27s ED stay. PVI was measured using the Masimo Radical-7®monitor (Masimo Corp., Irvine, CA). Results: Thirty-eight patients were recruited. Twenty-seven patients were discharged home, 10 patients were admitted to the general pediatrics floor and 1 patient was admitted to the intensive care unit. PVI values at triage did not correlate with disposition from the ED (p = 0.63). Additionally, when trending the change in PVI after 2 hours of therapy in the ED, no statistically significant patterns were demonstrated. Conclusions: Our study did not demonstrate a correlation between PVI and clinical course for asthmatics. PVI may be more clinically relevant in sicker children. Furthermore, it is possible that continuous monitoring of PVI may demonstrate more unique trends in relation to asthma severity versus single values of PVI. Additional studies are necessary to help clarify the relationship between PVI and the clinical course of children with SA

Treatment of Acute Gastroenteritis-Related Emesis with Bimodal Release Ondansetron

Background: There are 179 million cases of acute gastroenteritis (AGI) annually in the USA. In this study we tested a long-acting experimental 24 mg bimodal release ondansetron (BRO) pill which provides early serum levels similar to an 8mg immediate release tablet but sustains levels over 24 hours. We studied whether oral BRO improves 24 hour emesis related outcomes without the use of intravenous (IV) therapy among emergency department (ED) and urgent-care patients with AGI. Methods: This was a placebo-controlled double-blind randomized trial comparing the effects of BRO with a like-appearing placebo among patients \u3e12 years presenting to 19 EDs and 2 urgent-care centers with symptoms of AGI. Among inclusion criteria were \u3e2 episodes of emesis 4 hours prior to ED arrival, and duration of symptoms ≤ 36 hours. Among exclusion criteria were pregnancy, recent surgery, alcohol abuse, and an EKG QTC\u3e 450ms. The primary endpoint of treatment failure was defined as IV fluids given, vomiting, or rescue anti-emetics 30 minutes-24 hours after the first dose of study medication. Randomization was performed in a 3:2 treatment/placebo ratio after obtaining written consent and before any intervention. Patients with ED treatment success were discharged with a home diary and 3 additional study pills to use as needed. Statistical analyses included the Cochran Mantel Haenszel test and supporting logistic regression analyses. Odds ratios (OR) included 95% confidence intervals. Results: 321 patients were randomized with a mean age of 29.0 years. The intention to treat (ITT) analysis indicated treatment success of 66% (126/192) in the BRO group vs 54% (70/129) in the placebo group (OR 1.6 (1.02, 2.54) p=0.04). A per-protocol analysis found treatment success of 70% (123/177) vs 55% (67/122) in placebo (OR 1.87 (1.16, 3.02) p=0.01). Baseline nausea was a predictor of outcome (p=0.01) and was more severe in the treatment group. The ITT nausea-adjusted OR in favor of treatment was (1.78 (1.11, 2.86), p=0.02). Finally, the OR for treatment effect in ITT outcomes at 4 days after ED treatment was 1.47 (0.92, 2.35, p=0.10). Conclusion: This is the first study of AGI-related emesis showing benefit from any ondansetron preparation in adolescents and adults. Further, the study suggests AGI can be treated with a long-acting bimodal release tablet, potentially avoiding the need for IV access and repeat oral dosing

A 24 Milligram Bimodal Release Ondansetron Pill (RHB-102) Shows No Evidence of QT Interval Prolongation

Background: Ondansetron is first line treatment for vomiting and one of the most common medications in the ED setting. Concerns over the 32mg IV dose association with prolonged corrected QT interval (QTc) and torsades de pointes prompted an FDA warning in 2011. Still, there is a paucity of prospective data evaluating lower dose ondansetron in the acute care setting. As part of a double blind, placebo-controlled trial of a 24 mg bimodal release ondansetron (BRO) pill, we tested the safety of BRO compared to placebo on QTc change. The safety outcomes included either an increase in mean QTc or an increase in the proportion of patients with QTc change \u3e 30 msec. Methods: This was a planned safety outcome analysis within a multi-center, double blind, placebo-controlled trial. The trial compared the effects of BRO among patients â%o¥ 12 years, who presented to 19 EDs and 2 urgent-care centers with symptoms of acute gastroenteritis. The BRO provides early serum levels similar to an 8mg immediate release ondansetron tablet with sustained levels over 24 hours. Exclusion criteria were CHF, uncontrolled diabetes, recent surgery, alcohol and substance abuse, and a baseline EKG QTc\u3e 450ms. The safety endpoint for this analysis was the change in QTc interval at 4 hours following administration of study drug compared to baseline QTc. We calculated each QTc using both Bazett’s (QTcB) and Fredericia’s (QTcF) formulas. Statistical analyses included Chi Square and student’s t-test methods. Results: There were 156 patients who had ECG testing within the overall trial. The mean baseline QTcB in the BRO and placebo arms were 429.9 and 423.5 msec respectively. There was no difference in the change in QTcB at 4 hours post-study drug administration between the BRO (+1.1, 95% CI -2.9 to 5.2 msec) and placebo group (+4.4, 95% CI -0.2 to 9.0 msec). There was similarly no difference using the QTcF calculation. There were 4 (4.4%) patients in the BRO arm with a QTcB change \u3e 30 msec vs. 4 (7.1%) in the placebo arm (p=0.48). No patients in either arm had a QTcB change \u3e 60 msec after study drug administration. Conclusion: In patients with normal baseline QTc, bimodal extended release ondansetron caused no QTc prolongation in comparison to placebo. This supports previous post-marketing safety data for the currently available single dose short-acting oral formulation among patients without risk factors

Non-motor symptoms in atypical and secondary parkinsonism: the PRIAMO study

The PRIAMO study is a cross-sectional longitudinal observational study aimed at describing epidemiology and evolution of non-motor symptoms (NMS) in patients with different forms of parkinsonism recruited in 55 Italian centres and evaluated over 24 months. In this paper, we are reporting prevalence and clinical characteristics of NMS in patients with atypical and secondary parkinsonism. Out of 1307 consecutive patients with a diagnosis of parkinsonism, 83 patients had vascular parkinsonism (VP), 34 had multiple system atrophy (MSA), 30 had progressive supranuclear palsy (PSP), 14 had dementia with Lewy bodies (DLB) and 11 had corticobasal degeneration (CBD). MSA and DLB had the highest number of NMS domains and symptoms, respectively. Gastrointestinal symptoms, pain, urinary problems and postural instability due to orthostatic hypotension were most frequent in MSA. Sleep disturbances were also common with a prevalence of approximately 70% in all diagnostic groups but CBD (36%). Psychiatric symptoms and attention and memory impairment were frequently observed in all diagnoses but were most prevalent among DLB patients, whereas the prevalence of skin and respiratory disorders was rather low in all forms, ranging between 10 and 30%. Atypical parkinsonism patients also reported a low QoL, with no significant differences among the different forms, whereas PD and VP patients had a better QoL