Targeting oncogenic interleukin‐7 receptor signalling with N‐acetylcysteine in T cell acute lymphoblastic leukaemia

Activating mutations of the interleukin‐7 receptor (IL7R) occur in approximately 10% of patients with T cell acute lymphoblastic leukaemia (T‐ALL). Most mutations generate a cysteine at the transmembrane domain leading to receptor homodimerization through disulfide bond formation and ligand‐independent activation of STAT5. We hypothesized that the reducing agent N‐acetylcysteine (NAC), a well‐tolerated drug used widely in clinical practice to treat acetaminophen overdose, would reduce disulfide bond formation, and inhibit mutant IL7R‐mediated oncogenic signalling. We found that treatment with NAC disrupted IL7R homodimerization in IL7R‐mutant DND‐41 cells as assessed by non‐reducing Western blot, as well as in a luciferase complementation assay. NAC led to STAT5 dephosphorylation and cell apoptosis at clinically achievable concentrations in DND‐41 cells, and Ba/F3 cells transformed by an IL7R‐mutant construct containing a cysteine insertion. The apoptotic effects of NAC could be rescued in part by a constitutively active allele of STAT5. Despite using doses lower than those tolerated in humans, NAC treatment significantly inhibited the progression of human DND‐41 cells engrafted in immunodeficient mice. Thus, targeting leukaemogenic IL7R homodimerization with NAC offers a potentially effective and feasible therapeutic strategy that warrants testing in patients with T‐ALL.     

Outcomes of a type 2 diabetes education program adapted to the cultural contexts of Saudi women: A pilot study

Objective:

To explore the outcomes of a pilot intervention of a type 2 diabetes (T2D) education program, based on international standards, and adapted to the cultural and religious contexts of Saudi women.

Methods:

This study is an experiment of a pilot intervention carried out between August 2011 and January 2012 at the primary health clinics in Dammam. Women at risk of or diagnosed with T2D (N=35 including dropouts) were assigned to one of 2 groups; an intervention group participated in a pilot intervention of T2D education program, based on international standards and tailored to their cultural and religious contexts; and a usual care group received the usual care for diabetes in Saudi Arabia. Outcomes included blood glucose, body composition, 6-minute walk distance, life satisfaction, quality of life, and diabetes knowledge. The intervention group participated in a focus group of their program experience. Data analysis was based on mixed methods.

Results:

Based on 95% confidence interval comparisons, improvements were noted in blood sugar, 6-minute walk distance, quality of life, and diabetes knowledge in participants of the intervention group. They also reported improvements in lifestyle-related health behaviors after the education program.

Conclusion:

Saudi women may benefit from a T2D education program based on international standards and adapted to their cultural and religious contexts.Saudi women have a higher prevalence of obesity than men, which increases their risk of type 2 diabetes (T2D).1 The reporting of diabetes is higher in women compared to men in all provinces of Saudi Arabia.1 Diabetes education programs in Saudi Arabia do not target people at risk of diabetes with emphasis on diabetes prevention and feasible changes to lifestyle behaviors.2 Scientific evidence suggests that diabetes education programs based on international standards of lifestyle behaviors, are more effective when tailored to the cultures and religions of targeted groups.3-6 The aim of this study was to explore the outcomes of a pilot intervention of a T2D education program based on international standards and adapted to the cultural and religious contexts of Saudi women. Specifically, whether such a program can impact health outcomes (for example, physical health measures, diabetes knowledge, life satisfaction, and health-related quality of life, diabetes knowledge) in comparison with the usual care of T2D in Saudi Arabia.     

Risk factors for aortic valve dysfunction in children with discrete subvalvar aortic stenosis

Aortic regurgitation (AR) is a known complication of discrete subvalvar aortic stenosis (DSS), and its detection often triggers referral for surgery. However, risk factors for aortic valve dysfunction in children with DSS remain incompletely defined. The primary goal of this study was to determine independent risk factors for moderate or severe AR at mid-term follow-up in patients with DSS. Clinical records and echocardiograms of 220 patients with DSS (109 patients had DSS resection and 111 had no surgery) were analyzed. The primary outcome variable was AR grade (based on the width of the vena contracta) at latest follow-up. Age at diagnosis, gender, and duration of follow-up (median 7.2 years, range 1 to 20.4) did not differ significantly between medical and surgical patients. By multivariate analysis, independent risk factors for moderate to severe AR (n = 30) were older age at diagnosis of DSS (odds ratio [OR] for age > or =17 years 5.13, p = 0.024), previous balloon or surgical aortic valvuloplasty (OR 19.6, p <0.001), and a longer follow-up period (OR for 1-year increase 1.15, p = 0.032). Excluding patients with previous surgical or balloon aortic valvuloplasty, a higher maximal Doppler gradient was an independent risk factor for moderate to severe AR (OR for peak gradient > or =50 mm Hg 10.8, p = 0.001). Independent predictors of low-risk patients (none or trivial AR and peak gradient < or =30 mm Hg) included thin and mobile aortic valve leaflets (OR 7.86, p = 0.006) and an associated ventricular septal defect (OR 2.18, p = 0.019). These clinical and echocardiographic variables can be used to stratify risk of aortic valve dysfunction in patients with DSS and aid in timing of surgical resection.     

Is There a Recent Epidemic of Women's Drinking? A Critical Review of National Studies

Alcohol consumption is increasing in the United States, as is alcohol‐attributable mortality. Historically, men have had higher rates of alcohol consumption than women, though evidence for birth cohort effects on gender differences in alcohol consumption and alcohol‐related harm suggests that gender differences may be diminishing. We review studies using U.S. national data that examined time trends in alcohol consumption and alcohol‐related harm since 2008. Utilizing a historical–developmental perspective, here we synthesize and integrate the literature on birth cohort effects from varying developmental periods (i.e., adolescence, young adulthood, middle adulthood, and late adulthood), with a focus on gender differences in alcohol consumption. Findings suggest that recent trends in gender differences in alcohol outcomes are heterogeneous by developmental stage. Among adolescents and young adults, both males and females are rapidly decreasing alcohol consumption, binge and high‐intensity drinking, and alcohol‐related outcomes, with gender rates converging because males are decreasing consumption faster than females. This pattern does not hold among adults, however. In middle adulthood, consumption, binge drinking, and alcohol‐related harms are increasing, driven largely by increases among women in their 30s and 40s. The trend of increases in consumption that are faster for women than for men appears to continue into older adult years (60 and older) across several studies. We conclude by addressing remaining gaps in the literature and offering directions for future research.     

The functional response of infants with persistent wheezing to nebulized beclomethasone dipropionate

Lung function was measured in nine infants, ages 15-36 weeks, who had persistent wheezing, apparently following acute bronchiolitis, before and after 2 weeks of treatment with either inhaled nebulized beclomethasone dipropionate (BDP) or placebo in a randomized, double blind, crossover trial. The effect of nebulized albuterol (Salbutamol) was measured before and after the steroid treatment. Thoracic gas volume (TGV) and specific airway conductance (SGaw) were determined using a whole body plethysmograph, and forced expiratory flow at resting lung volume (VmaxFRC) was determined with a thoracoabdominal compression jacket. All infants had marked airways obstruction before treatment with mean +/- SE VmaxFRC of 24 +/- 4% predicted and SGaw of 37 +/- 5% predicted. Two weeks of placebo treatment had no significant effect on lung function, but after 2 weeks of BDP inhalation there was a significant rise in SGaw to 61 +/- 7% (P less than 0.005). VmaxFRC increased to 42 +/- 13% but the difference did not reach significance. Respiratory rate and clinical score for retractions and wheezing also fell significantly with BDP therapy (P less than 0.01 and P less than 0.001 respectively). Albuterol had no effect on lung function either before or during steroid therapy. Steroids may have a role in the management of persistent wheezing following bronchiolitis.     

Impact of left ventricular filling properties on the benefit of exercise training in patients with advanced chronic heart failure secondary to ischemic or nonischemic cardiomyopathy

This study examined left ventricular (LV) filling properties and exercise hemodynamics noninvasively before and after an exercise training program in patients with chronic heart failure (HF). Although exercise training did not improve LV filling properties in patients with advanced HF, LV filling properties determined the hemodynamic benefit attainable from exercise in this patient group.     

Morquio A Syndrome‐Associated Mutations: A Review of Alterations in the GALNS Gene and a New Locus‐Specific Database

Morquio A syndrome (mucopolysaccharidosis IVA) is an autosomal recessive disorder that results from deficient activity of the enzyme N‐acetylgalactosamine‐6‐sulfatase (GALNS) due to alterations in the GALNS gene, which causes major skeletal and connective tissue abnormalities and effects on multiple organ systems. The GALNS alterations associated with Morquio A are numerous and heterogeneous, and new alterations are continuously identified. To aid detection and interpretation of GALNS alterations, from previously published research, we provide a comprehensive and up‐to‐date listing of 277 unique GALNS alterations associated with Morquio A identified from 1,091 published GALNS alleles. In agreement with previous findings, most reported GALNS alterations are missense changes and even the most frequent alterations are relatively uncommon. We found that 48% of patients are assessed as homozygous for a GALNS alteration, 39% are assessed as heterozygous for two identified GALNS alterations, and in 13% of patients only one GALNS alteration is detected. We report here the creation of a locus‐specific database for the GALNS gene ( http://galns.mutdb.org/ ) that catalogs all reported alterations in GALNS to date. We highlight the challenges both in alteration detection and genotype–phenotype interpretation caused in part by the heterogeneity of GALNS alterations and provide recommendations for molecular testing of GALNS.     

Interpretation bias characterizes trait rumination

Background and objectives

Rumination, a maladaptive cognitive style of responding to negative mood, is thought to be maintained by a variety of cognitive biases. However, it is unknown whether rumination is characterized by interpretation biases.

Methods

Two experiments examined the link between rumination and interpretation biases, revealed in lexical-decision tasks (LDT). A homograph with both benign and ruminative or otherwise negative meaning was presented on each trial and followed by a letter string, to which participants responded by judging whether it was a word or a non-word. Letter strings were non-words or words related or unrelated to one meaning of the homograph.

Results

In both experiments, faster latencies to respond to targets related to the ruminative meaning of the homographs were produced by students with higher scores on self-report measures of rumination. Moreover, these biases were associated with both brooding, the maladaptive form of rumination, and reflection, the more adaptive component. No measure of rumination was significantly correlated with general biases toward negative meaning (Experiment 1) or with threatening interpretations of homographs (Experiment 2).

Limitations

The paucity of available rumination-related homographs dictated the use of non-fully randomized stimuli presentation (Experiment 1) or the use of only one set of the meanings associated with the homographs (Experiment 2).

Conclusions

Rumination is associated with a tendency to interpret ambiguous information in a rumination-consistent manner. This tendency may exacerbate ruminative thinking and can possibly be a target for future intervention.