The Course of Eating Disorders Involving Bingeing and Purging Among Adolescent Girls: Prevalence,Stability, and Transitions

Purpose

To quantify eating disorder (ED) stability and diagnostic transition among a community-based sample of adolescents and young adult females in the United States.

In vitro and in vivo mammalian mutation assays support a nonmutagenic mechanism of carcinogenicity for hydrazine

Hydrazine has been described as a mutagenic, probable human carcinogen. It is mutagenic in in vitro systems such as bacterial reverse mutation (Ames) tests and some yeast systems, as well as in in vivo systems with drosophila. It was shown to cause chromosome damage both in vitro and in vivo but was negative in some well‐validated mammalian mutation systems such as CHO HPRT assays. Importantly, there is only one in vivo gene mutation test reported, which was negative. Our objective was to determine if hydrazine is mutagenic in mammalian test systems. Thus, we conducted an in vitro gene mutation test in Muta?Mouse lung epithelial cells (FE1 cell assay) and a regulatory‐compliant in vivo Big Blue® mouse test. Consistent with previous reports, an additional six‐well Ames assay showed that hydrazine was mutagenic to bacteria. The FE1 cell assay was negative in conditions with and without metabolic activation when tested to cytotoxicity limits. In the Big Blue® mouse study, female mice received dosages of hydrazine up to 10.9 mg/kg via drinking water for 28 days. This dose is comparable to a dose used in a carcinogenicity study where female mice had significant increases in hepatocellular adenoma at 11.5 mg/kg. There were no increases in mutant frequency in liver and lung, two tissues sensitive to the carcinogenic effects of hydrazine in mice. Our research shows that hydrazine is not mutagenic in mammalian cells either in vitro or in vivo, indicating mutagenicity may not play a role in the carcinogenicity of hydrazine.     

The effect of caffeine abstinence on sleep among habitual caffeine users with poor sleep

Caffeine is the most widely used psychoactive substance in the world and is known to disrupt healthy sleep. However, very few studies have directly tested the effect of caffeine abstinence on sleep, and these have yielded inconsistent findings. The purpose of the present study was to examine changes in sleep following caffeine abstinence and examine the extent to which characteristics of habitual caffeine use moderated this change. Participants included 66 healthy, young adults with habitual caffeine use and poor sleep. During the 2‐week baseline, sleep was assessed using wrist actigraphy and daily caffeine use was assessed with bedtime diaries. Eligible participants then completed 1 week of caffeine abstinence, during which sleep was measured with wrist actigraphy. Multilevel models found no significant differences between either mean levels or growth trajectories of total sleep time or sleep efficiency between baseline and caffeine abstinence. Mean levels of sleep onset latency also did not differ between baseline and caffeine abstinence. A small but significant quadratic effect was observed, such that sleep onset latency decreased during the first few days of caffeine abstinence, then increased to levels above baseline. Characteristics of caffeine use did not moderate changes in sleep between baseline and caffeine abstinence. These data suggest that abstaining from caffeine may not result in long‐term sleep improvement for habitual caffeine users, which contradicts the common sleep health recommendation. The present findings encourage more rigorous investigation of the effectiveness of caffeine restriction on sleep.     

Enhanced sphingosine-1-phosphate receptor 2 expression underlies female CNS autoimmunity susceptibility

Multiple sclerosis (MS) is an inflammatory disease of the CNS that is characterized by BBB dysfunction and has a much higher incidence in females. Compared with other strains of mice, EAE in the SJL mouse strain models multiple features of MS, including an enhanced sensitivity of female mice to disease; however, the molecular mechanisms that underlie the sex- and strain-dependent differences in disease susceptibility have not been described. We identified sphingosine-1-phosphate receptor 2 (S1PR2) as a sex- and strain-specific, disease-modifying molecule that regulates BBB permeability by destabilizing adherens junctions. S1PR2 expression was increased in disease-susceptible regions of the CNS of both female SJL EAE mice and female patients with MS compared with their male counterparts. Pharmacological blockade or lack of S1PR2 signaling decreased EAE disease severity as the result of enhanced endothelial barrier function. Enhanced S1PR2 signaling in an in vitro BBB model altered adherens junction formation via activation of Rho/ROCK, CDC42, and caveolin endocytosis-dependent pathways, resulting in loss of apicobasal polarity and relocation of abluminal CXCL12 to vessel lumina. Furthermore, S1PR2-dependent BBB disruption and CXCL12 relocation were observed in vivo. These results identify a link between S1PR2 signaling and BBB polarity and implicate S1PR2 in sex-specific patterns of disease during CNS autoimmunity.     

Extending the phenotype associated with the CSNK2A1‐related Okur–Chung syndrome—A clinical study of 11 individuals

Variants in the Protein Kinase CK2 alpha subunit, encoding the CSNK2A1 gene, have previously been reported in children with an intellectual disability and dysmorphic facial features syndrome: now termed the Okur–Chung neurodevelopmental syndrome. More recently, through trio‐based exome sequencing undertaken by the Deciphering Developmental Disorders Study (DDD study), a further 11 children with de novo CSNK2A1 variants have been identified. We have undertaken detailed phenotyping of these patients. Consistent with previously reported patients, patients in this series had apparent intellectual disability, swallowing difficulties, and hypotonia. While there are some shared facial characteristics, the gestalt is neither consistent nor readily recognized. Congenital heart abnormalities were identified in nearly 30% of the patients, representing a newly recognized CSNK2A1 clinical association. Based upon the clinical findings from this study and the previously reported patients, we suggest an initial approach to the management of patients with this recently described intellectual disability syndrome.

     

Use of upper limb exercise to assess breathlessness in patients with cancer: tolerability, repeatability, and sensitivity

We report the development of an arm exercise test to assess breathlessness in patients with lung cancer who are breathless at low levels of exertion. Exercise consisted of raising the arm over 40 cm, either the dominant arm only (n=10) or both arms alternating at minute intervals (n=12). Subjects breathed through a mouthpiece, and ventilation (VE) and oxygen uptake (VO(2)) were measured. Following familiarization, three tests were performed over one week to explore repeatability, and sensitivity was assessed in a fourth test. Arm exercise was generally well tolerated and increased breathlessness, VE, and VO(2). The commonest factor limiting exercise was arm fatigue, although four patients in the two-arm test also reported breathlessness. Repeatability for breathlessness score and VE was best in the two-arm test. The added resistance used to assess sensitivity could not be detected. The two-arm test offers a potential means of assessing the effects of an intervention on breathlessness and E in patients for whom a cycle or treadmill exercise test is unsuitable.     

Pharmacokinetic-pharmacodynamic correlation from mouse to human with pazopanib, a multikinase angiogenesis inhibitor with potent antitumor and antiangiogenic activity

With the development of targeted therapeutics, especially for small-molecule inhibitors, it is important to understand whether the observed in vivo efficacy correlates with the modulation of desired/intended target in vivo. We have developed a small-molecule inhibitor of all three vascular endothelial growth factor (VEGF) receptors (VEGFR), platelet-derived growth factor receptor, and c-Kit tyrosine kinases, pazopanib (GW786034), which selectively inhibits VEGF-induced endothelial cell proliferation. It has good oral exposure and inhibits angiogenesis and tumor growth in mice. Because bolus administration of the compound results in large differences in C(max) and C(trough), we investigated the effect of continuous infusion of a VEGFR inhibitor on tumor growth and angiogenesis. GW771806, which has similar enzyme and cellular profiles to GW786034, was used for these studies due to higher solubility requirements for infusion studies. Comparing the pharmacokinetics by two different routes of administration (bolus p.o. dosing and continuous infusion), we showed that the antitumor and antiangiogenic activity of VEGFR inhibitors is dependent on steady-state concentration of the compound above a threshold. The steady-state concentration required for these effects is consistent with the concentration required for the inhibition of VEGF-induced VEGFR2 phosphorylation in mouse lungs. Furthermore, the steady-state concentration of pazopanib determined from preclinical activity showed a strong correlation with the pharmacodynamic effects and antitumor activity in the phase I clinical trial.