Detection of a novel RYR1 mutation in four malignant hyperthermia pedigrees

Malignant hyperthermia (MH) is a potentially fatal autosomal dominant disorder of skeletal muscle and is triggered in susceptible people by all commonly used inhalational anaesthetics and depolarizing muscle relaxants. To date, six mutations in the skeletal muscle ryanodine receptor gene (RYR1) have been identified in malignant hyperthermia susceptible (MHS) and central core disease (CCD) cases. Using SSCP analysis, we have screened the RYR1 gene in affected individuals for novel MHS mutations and have identified a G to A transition mutation which results in the replacement of a conserved Gly at position 2433 with an Arg. The Gly2433Arg mutation was present in four of 104 unrelated MHS individuals investigated and was not detected in a normal population sample. This mutation is adjacent to the previously identified Arg2434His mutation reported in a CCD/MH family and indicates that there may be a second region in the RYR1 gene where MHS/CCD mutations cluste

Kpc-Scale Neutral Iron Kα\alpha Emission in the Starburst-AGN NGC 4945: a Relic AGN Outflow?

NGC 4945 contains a well-known heavily obscured active galactic nucleus (AGN) at its core, with prior reports of strong nuclear and off-nuclear neutral Fe K$\alpha$ emission due to the AGN activity. We report the discovery of very extended Fe K$\alpha$ emission with the XMM-Newton EPIC pn in a $\sim5$ kpc by $\sim10$ kpc region that is misaligned with the plane of the inclined optical galaxy disk by $\sim60$ degrees in projection. After a careful consideration of the crowded center of the galaxy and numerous unresolved hard X-ray sources present, we estimate that $\sim15$% of the Fe K$\alpha$ is extended on kpc-sized scales. The overall size and misalignment of the region follows an unusual pattern of radio polarization that is not typical of starbursts or normal disk galaxies but has been interpreted as possibly due to AGN activity. We suggest that the extended Fe K$\alpha$ emission arose from a period of AGN eruption several million years ago - a relic of a past AGN ejection episode.Comment: 24 pages including figures and tables, 12 figures, 3 tables. Submitted to ApJ, under revie

One-Antigen Mismatched Related versus HLA-Matched Unrelated Donor Hematopoietic Stem Cell Transplantation in Adults with Acute Leukemia: Center for International Blood and Marrow Transplant Research Results in the Era of Molecular HLA Typing

Approximately 13% of patients lacking an HLA-identical sibling have a one-antigen–mismatched related donor (MMRD). Historically, outcomes from the use of a one-antigen MMRD were considered equivalent to those from the use of a matched unrelated donor (UD). Recent improvements in UD stem cell transplantation (SCT) resulting from better molecular HLA matching justifies investigating whether UD should be preferred over MMRD in adult patients with acute leukemia. Here, we compared the outcomes of MMRD (n = 89) and HLA-A, -B, -C, and -DRB1 allele–matched UD (n = 700) SCT reported to the Center for International Blood and Marrow Transplant Research between 1995 and 2005. The patients underwent transplantation for acute myelogenous leukemia or acute lymphoblastic leukemia in first or second complete remission. Donor type was not associated with hematologic recovery. Univariate and multivariate comparisons of MMRD versus HLA-matched UD transplants showed no statistically significant differences in overall survival, disease-free survival, treatment-related mortality, relapse, or 100-day grade III-IV acute graft-versus-host disease (GVHD). MMRD SCT was associated with a lower rate of chronic GVHD at 1 year (35% vs 47%; P = .03), which was confirmed by multivariate analysis (relative risk, 0.58; 95% confidence interval, 0.39-0.85; P < .01). According to our data, HLA-matched UD and MMRD SCT are associated with comparable survival. Given that less chronic GVHD was observed in the MMRD transplantations, this option, when available, remains the first choice in patients with acute leukemia without an HLA-identical sibling in need of allogeneic SCT

Methylphenidate and Sleep Difficulties in Children and Adolescents With ADHD: Results From the 2-Year Naturalistic Pharmacovigilance ADDUCE Study

Objective: Short-term RCTs have demonstrated that MPH-treatment significantly reduces ADHD-symptoms, but is also associated with adverse events, including sleep problems. However, data on long-term effects of MPH on sleep remain limited. Methods: We performed a 2-year naturalistic prospective pharmacovigilance multicentre study. Participants were recruited into three groups: ADHD patients intending to start MPH-treatment (MPH-group), those not intending to use ADHD-medication (no-MPH-group), and a non-ADHD control-group. Sleep problems were assessed with the Children’s-Sleep-Habits-Questionnaire (CSHQ). Results: 1,410 participants were enrolled. Baseline mean CSHQ-total-sleep-scores could be considered clinically significant for the MPH-group and the no-MPH-group, but not for controls. The only group to show a significant increase in any aspect of sleep from baseline to 24-months was the control-group. Comparing the MPH- to the no-MPH-group no differences in total-sleep-score changes were found. Conclusion: Our findings support that sleep-problems are common in ADHD, but don’t suggest significant negative long-term effects of MPH on sleep

Reports of Perceived Adverse Events of Stimulant Medication on Cognition, Motivation, and Mood:Qualitative Investigation and the Generation of Items for the Medication and Cognition Rating Scale

Items were identified that capture potential/perceived cognitive, motivational, and mood-related adverse events of MPH. The items generated will allow us to further develop and psychometrically examine their prevalence, and the extent to which they are associated with medication adherence, treatment outcome, impairment, and other reported adverse events (e.g., loss of appetite/cardiovascular effects)

The First Definitive Binary Orbit Determined with the Hubble Space Telescope Fine Guidance Sensors: Wolf 1062 (Gliese 748)

The M dwarf binary, Wolf 1062 (Gliese 748), has been observed with the Hubble Space Telescope (HST) Fine Guidance Sensor 3 in the transfer function scan mode to determine the apparent orbit. This is the first orbit defined fully and exclusively with HST, and is the most accurate definitive orbit for any resolved, noneclipsing system. The orbital period is 2.4490 ± 0.0119 yr and the semimajor axis is 01470 ± 00007—both quantities are now known to better than 1%. Using the weighted mean of seven parallax measurements and these HST data, we find the system mass to be 0.543 ± 0.031 M⊙, where the error of 6% is due almost entirely to the parallax error. An estimated fractional mass from the infrared brightness ratio and infrared mass-luminosity relation yields a mass for the primary of 0.37 M⊙, and the secondary falls in the regime of very low mass stars, with a mass of only 0.17 M⊙

The Impact of Methylphenidate on Pubertal Maturation and Bone Age in ADHD Children and Adolescents: Results from the ADHD Drugs Use Chronic Effects (ADDUCE) Project

Objective: The short-term safety of methylphenidate (MPH) has been widely demonstrated; however the long-term safety is less clear. The aim of this study was to investigate the safety of MPH in relation to pubertal maturation and to explore the monitoring of bone age.// Method: Participants from ADDUCE, a two-year observational longitudinal study with three parallel cohorts (MPH group, no-MPH group, and a non-ADHD control group), were compared with respect to Tanner staging. An Italian subsample of medicated-ADHD was further assessed by the monitoring of bone age.// Results: The medicated and unmedicated ADHD groups did not differ in Tanner stages indicating no higher risk of sexual maturational delay in the MPH-treated patients. The medicated subsample monitored for bone age showed a slight acceleration of the bone maturation after 24 months, however their predicted adult height remained stable.// Conclusion: Our results do not suggest safety concerns on long-term treatment with MPH in relation to pubertal maturation and growth

The Impact of Methylphenidate on Pubertal Maturation and Bone Age in ADHD Children and Adolescents:Results from the ADHD Drugs Use Chronic Effects (ADDUCE) Project

Objective: The short-term safety of methylphenidate (MPH) has been widely demonstrated; however the long-term safety is less clear. The aim of this study was to investigate the safety of MPH in relation to pubertal maturation and to explore the monitoring of bone age.Method: Participants from ADDUCE, a two-year observational longitudinal study with three parallel cohorts (MPH group, no-MPH group, and a non-ADHD control group), were compared with respect to Tanner staging. An Italian subsample of medicated-ADHD was further assessed by the monitoring of bone age.Results: The medicated and unmedicated ADHD groups did not differ in Tanner stages indicating no higher risk of sexual maturational delay in the MPH-treated patients. The medicated subsample monitored for bone age showed a slight acceleration of the bone maturation after 24 months, however their predicted adult height remained stable.Conclusion: Our results do not suggest safety concerns on long-term treatment with MPH in relation to pubertal maturation and growth.</p