Ph-negative chronic myeloid leukemia: molecular analysis of ABL insertion into M-BCR on chromosome 22

Leukemic cells from a patient with Ph-negative chronic myeloid leukemia (CML) had a normal karyotype. M-BCR was rearranged and chromosome in situ hybridization showed an ABL insertion between 5' and 3' M-BCR on an apparently normal chromosome 22. The association of 5' BCR and 3' ABL at the 5' junction of the chromosome 9 insert was typical of that found for the BCR-ABL fusion gene in other patients with the standard t(9;22) and CML. With an M-bcr-3' probe, we cloned and characterized a 3' junction fragment. Field inversion gel electrophoresis and chromosome in situ hybridization studies using a probe isolated from genomic DNA 5' of the junction showed that 3' M-BCR was joined to a region of chromosome 9q34 rich in repetitive sequences and lying some distance 3' of ABL. The chromosome 9 insert was at least 329 kilobases long and included 3' ABL and a larger portion of chromosome 9q34. Our results allowed us to exclude transposon- or retroviral-mediated insertion of ABL into chromosome 22. Instead, we favored a two-translocation model in which a second translocation reconstituted a standard t(9;22)(q34;q11) but left the chromosome 9 insert, including 3' ABL, in chromosome 22.     

Sleep problems in early childhood and early onset of alcohol and other drug use in adolescence

BACKGROUND: No prospective studies exist on the relationship between sleep problems early in life and subsequent alcohol use. Stimulated by the adult literature linking sleep problems to the subsequent onset of alcohol use disorders in some adults, we examined whether sleep problems in early childhood predicted the onset of alcohol and other drug use in adolescence and whether such a relationship was mediated by other known predictors of this relationship, namely, attention problems, anxiety/depression, and aggression in late childhood. METHODS: This study is part of an ongoing longitudinal study of the development of risk for alcohol and other substance use disorders. Study participants were 257 boys from a community-recruited sample of high-risk families. RESULTS: Mothers' ratings of their children's sleep problems at ages 3 to 5 years significantly predicted an early onset of any use of alcohol, marijuana, and illicit drugs, as well as an early onset of occasional or regular use of cigarettes by age 12 to 14. Additionally, although sleep problems in early childhood also predicted attention problems and anxiety/depression in later childhood, these problems did not mediate the relationship between sleep problems and onset of alcohol and other drug use. CONCLUSIONS: This is, to our knowledge, the first study that prospectively examines the relationship between sleep problems and early onset of alcohol use, a marker of increased risk for later alcohol problems and alcohol use disorders. Moreover, early childhood sleep problems seem to be a robust marker for use of drugs other than alcohol. Implications for the prevention of early alcohol and other drug use are discussed.     

Relationship of systolic BP to obstructive sleep apnea in patients with heart failure

STUDY OBJECTIVES: Obstructive sleep apnea (OSA) is an independent risk factor for hypertension in the general population. Hypertension is, in turn, an important risk factor for the development and progression of congestive heart failure (CHF). Our objective was to determine whether OSA would be associated with elevated daytime BP in medically treated patients with CHF. DESIGN: Cross-sectional study. SETTING: Tertiary care, university-affiliated sleep disorders and heart failure clinics. PATIENTS: Three hundred one consecutive patients with CHF. MEASUREMENTS AND RESULTS: We measured daytime BP and performed overnight sleep studies to assess for the presence of OSA. Among these patients, OSA was present in 121 patients (40%) and their systolic BP was significantly higher than in patients without OSA. Patients with OSA were 2.89 times (95% confidence interval, 1.25 to 6.73) more likely to have systolic hypertension (ie, BP > or = 140 mm Hg) than those without OSA after controlling for other risk factors, including obesity. The degree of systolic BP elevation was directly related to the frequency of obstructive apneas and hypopneas. CONCLUSIONS: In medically treated patients with CHF, daytime systolic BP and the prevalence of systolic hypertension are significantly increased in patients with OSA, compared to those without OSA, independent of other potentially confounding factors. OSA may therefore have contributed to the presence of systolic hypertension in some of these patients.     

The Contribution of Anxiety Sensitivity to Obsessive–Compulsive and Anxiety Symptoms in a Naturalistic Treatment Setting

Anxiety sensitivity (AS), a fear of arousal-related sensations, is prevalent in a number of disorders. We examined the relationship between internalizing symptoms and the anxiety sensitivity components of physical, social, and cognitive concerns in a sample of 165 patients seeking treatment in a clinic specializing in cognitive behavioral therapy for anxiety-related disorders. Social anxiety symptoms were associated with greater social concerns. Cognitive concerns were characteristic of both depression and generalized anxiety symptoms, suggesting these two classes of symptoms may share AS symptomatology. Physical concerns were specifically related to panic symptoms. Although obsessive–compulsive symptoms were related to cognitive concerns using univariate regression, these symptoms were not strongly related to any of the anxiety sensitivity components when the correlation between disorders was taken into account. Thus, within the internalizing symptoms studied here, the anxiety sensitivity domains were most relevant to panic, social anxiety, generalized anxiety, and depressive symptoms and less related to obsessive–compulsive symptoms.     

Novel Approaches to Improve the Intrinsic Microbiological Safety of Powdered Infant Milk Formula

Human milk is recognised as the best form of nutrition for infants. However; in instances where breast-feeding is not possible, unsuitable or inadequate, infant milk formulae are used as breast milk substitutes. These formulae are designed to provide infants with optimum nutrition for normal growth and development and are available in either powdered or liquid forms. Powdered infant formula is widely used for convenience and economic reasons. However; current manufacturing processes are not capable of producing a sterile powdered infant formula. Due to their immature immune systems and permeable gastro-intestinal tracts, infants can be more susceptible to infection via foodborne pathogenic bacteria than other age-groups. Consumption of powdered infant formula contaminated by pathogenic microbes can be a cause of serious illness. In this review paper, we discuss the current manufacturing practices present in the infant formula industry, the pathogens of greatest concern, Cronobacter and Salmonella and methods of improving the intrinsic safety of powdered infant formula via the addition of antimicrobials such as: bioactive peptides; organic acids; probiotics and prebiotics.     

Development of toxicity values and exposure estimates for tetrabromobisphenol A: application in a margin of exposure assessment

Tetrabromobisphenol A (TBBPA) is used in a diverse array of products to improve fire safety. The National Toxicology Program (NTP) recently completed a 2‐year bioassay for TBBPA. The objective of the present study was to develop a cancer‐based and a non‐cancer based toxicity value and to compare such to appropriate estimates of human exposure. Data from the NTP 2‐year and 13‐week studies were selected to develop candidate toxicity values. Benchmark dose modeling and subsequent evaluation of candidate values resulted in selection of an oral reference dose (RfD) of 0.6 mg kg^?1 day^?1 based on uterine hyperplasia in rats and an oral cancer slope factor (OSF) of 0.00315 per mg kg^?1 day^?1 based on an increased incidence of uterine tumors in rats. Lifetime average daily dose (LADD) estimates ranged from 2.2 E^?7 to 3.9 E^?6 mg kg^?1 day^?1 based on age‐adjusted exposures to TBBPA via breast milk consumption, dietary intake, soil/dust ingestion and drinking water ingestion in infants, young children, older children and adults. Average daily dose (ADD) estimates ranged from 3.2 E ^?7 to 8.4 E^?5 mg kg^?1 day^?1. Resulting margin of exposure (MOE) values were > 800 000 for non‐cancer endpoints and > 32 000 000 for cancer‐based endpoints. These data collectively indicate a low level of health concern associated with exposures to TBBPA based on current data. It is anticipated that the exposure estimates, along with the toxicity values described within, should be informative for understanding human health hazards associated with TBBPA. Copyright © 2015. The Authors. Journal of Applied Toxicology Published by John Wiley & Sons Ltd.     

The assessment and management of patients with acute asthma.

Acute asthma is a common medical emergency that is often poorly assessed and managed. Initial evaluation should include a review of historical factors for identifying high risk patients; appropriate evaluation of the current exacerbation, including an objective assessment of airflow obstruction; and, in parallel, initiation of therapy with controlled oxygen therapy, regular bronchodilator therapy and, in most cases, systemic corticosteroids. There is no benefit in using intravenous (IV) corticosteroids--a single 50 mg oral dose is appropriate. Although there is no significant additional bronchodilator effect with the use of ipratropium bromide or IV magnesium, both modalities have been shown to reduce hospitalisations for moderate to severe exacerbations. There is no role for the routine use of IV aminophylline or beta (beta) agonists in patients presenting with acute asthma. Patients who achieve 60% of their predicted peak expiratory flow (PEF) or 1 sec forced expiratory volume (FEV1) or best can usually be safely discharged. The exacerbation should be taken as an opportunity to review how a patient responded to the particular exacerbation. Were they on appropriate anti-inflammatory therapy? Did they modify the dose of therapy early in the exacerbation? Did they have an action plan? Such deficiencies can usually be managed by facilitated referral to a specialist clinic that ideally has an asthma education programme. The need for long-term anti-inflammatory therapy can be reviewed at this time as well as the potential incremental benefit of the addition of add-on therapy, most likely the use of a long-acting beta agonist.     

New developments in intravascular ultrasound

Intravascular ultrasound (IVUS) is a dynamic imaging modality that provides real-time in vivo visualization of atherosclerosis and other vascular pathology. The tomographic image presentation of IVUS permits detailed assessment of plaque morphology and its corresponding responses to interventional therapy. IVUS studies have confirmed vascular remodeling in vivo, have proposed a high-pressure stent implantation strategy and have shown two key mechanisms of restenosis after angioplasty: plaque proliferation and vessel shrinkage (negative remodeling). IVUS also provides accurate quantitative information regarding lumen size, vessel size and plaque burden. These observations, essential to achieving improved outcomes, have drastically changed the understanding of atherosclerotic artery disease and interventional procedures. IVUS has matured into an essential complement to daily peripheral and coronary interventional practice and is routinely incorporated as part of the interventional arsenal in the catheterization laboratory. A variety of new imaging techniques are currently being designed and tested. These include combined therapeutic devices, further miniaturization, 3-D applications and tissue characterization. These techniques may evolve to provide increased favorable clinical outcomes and more accurate information of vessel geometry and plaque composition.