A splice site and copy number variant responsible for TTC25-related primary ciliary dyskinesia.

Primary ciliary dyskinesia (PCD) is a genetically heterogeneous disorder of motile cilia. With few exceptions, PCD is an autosomal recessive condition, and there are over 40 genes associated with the condition. We present a case of a newborn female with clinical features of PCD, specifically the Kartagener syndrome phenotype, due to variants in TTC25. This gene has been previously associated with PCD in three families. Two multi-gene panels performed as a neonate and at two years of age were uninformative. Exome sequencing was performed by the Care4Rare Canada Consortium on a research basis, and an apparent homozygous intronic variant (TTC25:c.1145+1G > A) was identified that was predicted to abolish the canonical splice donor activity of exon 8. The child's mother was a heterozygous carrier of the variant. The paternal sample did not show the splice variant, and homozygosity was observed across the paternal locus. Microarray analysis showed a 50 kb heterozygous deletion spanning the genes TTC25 and CNP. This is the first example of a pathogenic gross deletion in trans with a splice variant, resulting in TTC25-related PCD.

The impact of new-onset cancer among veterans who are receiving warfarin for atrial fibrillation and venous thromboembolism.

BACKGROUND: A new cancer diagnosis adds significant complexity and uncertainty to the management of pre-existing warfarin therapy. OBJECTIVES: To determine how new-onset cancer affects anticoagulation control and outcomes among patients who had been receiving warfarin for atrial fibrillation (AF) compared to patients who had been receiving warfarin for venous thromboembolism (VTE) prior to cancer diagnosis. PATIENTS/METHODS: This cohort study started with 122,875 veterans who had been receiving warfarin for at least six months from a VA Medical Center between 10/1/06 and 9/30/08. We identified patients with incident cancer during this interval, and excluded those with a prior cancer history. We analyzed percent time in therapeutic range (TTR) at 6 and 12-month intervals after cancer diagnosis compared to pre-cancer baseline, as well as crude rates of warfarin-relevant outcomes (stroke, major bleeding, mortality) between patients with AF and VTE. RESULTS: Among patients with new-onset cancer, patients anticoagulated for AF outnumbered those anticoagulated for VTE more than 2.5-fold. There were no significant differences in TTR by indication for warfarin in months 0-6 or 7-12 following cancer diagnosis, but TTR decreased significantly compared to the pre-cancer baseline for both groups in months 0-6. As expected, cancer patients with VTE had significantly worse mortality at six months and one year compared to cancer patients with AF. CONCLUSION: Patients receiving chronic warfarin therapy who are newly diagnosed with cancer experience a significant decrease in TTR in the first 6months after diagnosis, regardless of indication for anticoagulation. This effect appears to attenuate in months 7-12.

INR targets and site-level anticoagulation control: results from the Veterans AffaiRs Study to Improve Anticoagulation (VARIA).

BACKGROUND: Not all clinicians target the same International Normalized Ratio (INR) for patients with a guideline-recommended target range of 2-3. A patient's mean INR value suggests the INR that was actually targeted. We hypothesized that sites would vary by mean INR, and that sites of care with mean values nearest to 2.5 would achieve better anticoagulation control, as measured by per cent time in therapeutic range (TTR). OBJECTIVES: To examine variations among sites in mean INR and the relationship with anticoagulation control in an integrated system of care. PATIENTS/METHODS: We studied 103,897 patients receiving oral anticoagulation with an expected INR target between 2 and 3 at 100 Veterans Health Administration (VA) sites from 1 October 2006 to 30 September 2008. Key site-level variables were: proportion near 2.5 (that is, percentage of patients with mean INR between 2.3 and 2.7) and mean risk-adjusted TTR. RESULTS: Site mean INR ranged from 2.22 to 2.89; proportion near 2.5, from 30 to 64%. Sites' proportions of patients near 2.5, below 2.3 and above 2.7 were consistent from year to year. A 10 percentage point increase in the proportion near 2.5 predicted a 3.8 percentage point increase in risk-adjusted TTR (P < 0.001). CONCLUSIONS: Proportion of patients with mean INR near 2.5 is a site-level 'signature' of care and an implicit measure of targeted INR. This proportion varies by site and is strongly associated with site-level TTR. Our study suggests that sites wishing to improve TTR, and thereby improve patient outcomes, should avoid the explicit or implicit pursuit of non-standard INR targets.

Patient characteristics associated with oral anticoagulation control: results of the Veterans AffaiRs Study to Improve Anticoagulation (VARIA).

BACKGROUND: In patients receiving oral anticoagulation, improved control can reduce adverse outcomes such as stroke and major hemorrhage. However, little is known about patient-level predictors of anticoagulation control. OBJECTIVES: To identify patient-level predictors of oral anticoagulation control in the outpatient setting. PATIENTS/METHODS: We studied 124,619 patients who received oral anticoagulation from the Veterans Health Administration from October 2006 to September 2008. The outcome was anticoagulation control, summarized using percentage of time in therapeutic International Normalized Ratio range (TTR). Data were divided into inception (first 6 months of therapy; 39,447 patients) and experienced (any time thereafter; 104,505 patients). Patient-level predictors of TTR were examined by multivariable regression. RESULTS: Mean TTRs were 48% for inception management and 61% for experienced management. During inception, important predictors of TTR included hospitalizations (the expected TTR was 7.3% lower for those with two or more hospitalizations than for the non-hospitalized), receipt of more medications (16 or more medications predicted a 4.3% lower than for patients with 0-7 medications), alcohol abuse (-4.6%), cancer (-3.1%), and bipolar disorder (-2.9%). During the experienced period, important predictors of TTR included hospitalizations (four or more hospitalizations predicted 9.4% lower TTR), more medications (16 or more medications predicted 5.1% lower TTR), alcohol abuse (-5.4%), female sex (- 2.9%), cancer (-2.7%), dementia (-2.6%), non-alcohol substance abuse (-2.4%), and chronic liver disease (-2.3%). CONCLUSIONS: Some patients receiving oral anticoagulation therapy are more challenging to maintain within the therapeutic range than others. Our findings can be used to identify patients who require closer attention or innovative management strategies to maximize benefit and minimize harm from oral anticoagulation therapy.

Treating asthma with omega-3 fatty acids: where is the evidence? A systematic review.

BACKGROUND: Considerable interest exists in the potential therapeutic value of dietary supplementation with the omega-3 fatty acids. Given the interplay between pro-inflammatory omega-6 fatty acids, and the less pro-inflammatory omega-3 fatty acids, it has been thought that the latter could play a key role in treating or preventing asthma. The purpose was to systematically review the scientific-medical literature in order to identify, appraise, and synthesize the evidence for possible treatment effects of omega-3 fatty acids in asthma. METHODS: Medline, Premedline, Embase, Cochrane Central Register of Controlled Trials, CAB Health, and, Dissertation Abstracts were searched to April 2003. We included randomized controlled trials (RCT's) of subjects of any age that used any foods or extracts containing omega-3 fatty acids as treatment or prevention for asthma. Data included all asthma related outcomes, potential covariates, characteristics of the study, design, population, intervention/exposure, comparators, and co interventions. RESULTS: Ten RCT's were found pertinent to the present report. CONCLUSION: Given the largely inconsistent picture within and across respiratory outcomes, it is impossible to determine whether or not omega-3 fatty acids are an efficacious adjuvant or monotherapy for children or adults. Based on this systematic review we recommend a large randomized controlled study of the effects of high-dose encapsulated omega-3 fatty acids on ventilatory and inflammatory measures of asthma controlling diet and other asthma risk factors. This review was limited because Meta-analysis was considered inappropriate due to missing data; poorly or heterogeneously defined populations, interventions, intervention-comparator combinations, and outcomes. In addition, small sample sizes made it impossible to meaningfully assess the impact on clinical outcomes of co-variables. Last, few significant effects were found.

Assessing the efficacy of a school-based asthma education program for children: a pilot study.

BACKGROUND: Asthma diminishes the health-related quality of life for many school-aged children. This study sought to explore the effect of a School-Based Asthma Education Program (SBAEP) on quality of life. METHODS: Children with asthma who attended grades 1-5 at two selected schools were requested to participate in this pilot study. Participants at one school were provided with a SBAEP, those at another school (control group) were provided with written educational material about asthma. The children completed the Paediatric Asthma Quality of Life Questionnaire (PAQLQ) before and one month after the educational interventions. RESULTS: There were clinically important improvements in the SBAEP group in quality of life, specifically in the symptom subdomain. CONCLUSIONS: The "Air Force" SBAEP appears to result in a favourable trend in quality of life for children. A larger scale trial is required following revisions to the program.

A comparison of inhaled fluticasone and oral prednisone for children with severe acute asthma.

BACKGROUND: Inhaled corticosteroids are effective in the treatment of children with asthma. It is uncertain how inhaled corticosteroids compare with oral corticosteroids in the management of severe acute disease. METHODS: We performed a double-blind, randomized trial involving 100 children five years of age or older who had severe acute asthma (indicated by a forced expiratory volume in one second [FEV1] that was less than 60 percent of the predicted value) and in whom the results could be evaluated. All were treated with an aggressive bronchodilator regimen and received one dose of either 2 mg of inhaled fluticasone through a metered-dose inhaler with a spacer or 2 mg of oral prednisone per kilogram of body weight. They were assessed hourly for up to four hours. RESULTS: The mean (+/-SD) base-line FEV1 as a percentage of the predicted value was 46.3+/-12.5 in the fluticasone group (51 subjects) and 43.9+/-9.9 in the prednisone group (49 subjects). The FEV1 increased by a mean of 9.4+/-12.5 percentage points in the fluticasone group and by 18.9+/-9.8 percentage points in the prednisone group four hours after therapy (P< 0.001). None of the children in the prednisone group had a reduction in FEV1 as a percentage of the predicted value from base line to four hours, as compared with 25 percent of those in the fluticasone group (P<0.001). Sixteen (31 percent) of the children treated with fluticasone were hospitalized, as compared with five (10 percent) of those treated with prednisone (P=0.01). CONCLUSIONS: Children with severe acute asthma should be treated with oral prednisone and not with inhaled fluticasone or a similar inhaled corticosteroid.

A randomized controlled trial of a 3-year home exercise program in cystic fibrosis.

OBJECTIVES: To evaluate the effects of a 3-year home exercise program on pulmonary function and exercise tolerance in mildly to moderately impaired patients with cystic fibrosis (CF) and to assess whether regular aerobic exercise is a realistic treatment option. STUDY DESIGN: Seventy-two patients with CF (7-19 years) were randomly assigned to an exercise group (a minimum of 20 minutes of aerobic exercise, at a heart rate of approximately 150 beats/min, 3 times weekly) or a control group (usual physical activity participation). Pulmonary function, exercise tolerance, clinical status, hospitalizations, and compliance with therapy were monitored during scheduled visits to the hospital's CF clinic. RESULTS: Sixty-five patients were included in the analyses. The control group demonstrated a greater annual decline in percent of predicted forced vital capacity compared with the exercise group (mean slope +/- SD, -2.42 +/- 4.15 vs -0.25 +/- 2.81; P =.02), with a similar trend for forced expiratory volume in 1 second (-3.47 +/- 4.93 vs -1.46 +/- 3. 55; P =.07). Patients remained compliant with the exercise program over the study period. An improved sense of well-being was reported with exercise. CONCLUSIONS: Pulmonary function declined more slowly in the exercise group than in the control group, suggesting a benefit for patients with CF participating in regular aerobic exercise. Consistent compliance with the home exercise program and a self-reported positive attitude toward exercise provide further evidence of the feasibility and value of including an aerobic exercise program in the conventional treatment regimen of patients with CF.

Does ketotifen have a steroid-sparing effect in childhood asthma?

In view of the possible systemic side-effects of inhaled corticosteroids (ICS), a study was performed to determine whether ketotifen (versus placebo) can replace or allow a reduction in the dose of ICS required for the maintenance treatment of childhood asthma. Sixty six children (aged 6-13 yrs) with asthma (confirmed by methacholine challenge), who were maintained on ICS, at a dose of < or = 1 mg.day-1, were selected, and 52 subjects completed the trial. Children on long-term oral steroids or cromoglycate were excluded. After a 4 week baseline period, the children were randomized to receive ketotifen, 2 mg.day-1, or placebo for 32 Weeks. Between weeks 13-20 of the study, the daily dose of steroid was tapered by 25% every second week to the minimum dose tolerated by the patients. For the remainder of the study (Weeks 21-32) the patients continued on this dose (if tolerated). Beta 2-agonists were allowed, as necessary, for symptom relief. During the baseline period, the mean daily ICS dosage was 432 micrograms in the ketotifen group versus 408 micrograms in the placebo group (NS). Among the-patients who completed the study, the average ICS dosage during the final phase of the study (Weeks 21-32) was only 18% of baseline in the ketotifen group versus 35% in the placebo group (NS). Lung function, diurnal variability in peak flow rates and methacholine sensitivity (provocative concentration producing a 20% fall in forced expiratory volume in one second (PC20)) remained unchanged in both groups throughout the study. During the last 12 weeks of the study, the ketotifen-treated patients were symptomatically better controlled. In the present study, ketotifen did not have a greater steroid-sparing effect than placebo.

Maximal expiratory flows generated by rapid chest compression following end-inspiratory occlusion or expiratory clamping in young children.

Partial forced expiratory flow-volume curves obtained by the rapid chest compression technique are being widely used to assess pulmonary function in infants and young children. The aim of this study is to assess whether in this age group flow limitation is achieved with the partial forced expiratory flow-volume curve with rapid chest compression. In eight infants and young children sedated with chloral hydrate, flow-volume curves were obtained by regular rapid chest compression technique, end-inspiratory airway occlusion prior to rapid chest compression, and expiratory clamping prior to rapid chest compression. In each technique, beginning with a cuff pressure of 20 cmH2O, the cuff pressure was increased by 10 cmH2O increments until the compression pressure reached 90 cmH2O. Maximal flow-volume curves were generated by each technique. End-inspiratory occlusion prior to rapid chest compression caused higher flows over the entire phase of expiration than the regular rapid chest compression. This increase could be observed over the entire phase of expiration. Forced expiratory flow at 50% and at 75% of vital capacity (V50 and V75) with regular rapid chest compression were 207 +/- 44 ml.s-1 (mean +/- SD) and 138 +/- 59 ml.sec-1, respectively. When end-inspiratory occlusion preceded rapid chest compression, V50 and V75 increased to 283 +/- 114 and 206 +/- 61 ml.sec-1 respectively, with a mean increase in V50 of 34% and in V75 of 31%. When expiratory clamping preceded the compression, even higher expiratory flows resulted.(ABSTRACT TRUNCATED AT 250 WORDS)

Proton and nitrogen NMR sequence-specific assignments and secondary structure determination of the Bacillus subtilis SPO1-encoded transcription factor 1.

Sequence-specific 1H and 15N NMR1 assignments are reported for the transcription factor 1 (TF1), a 22-kDa type II DNA-binding protein (DBPII) that consists of two 99-residue monomers. An assignment strategy is employed that uses six complementary selectively deuterium-labeled TF1 variants and an uniformly 15N-labeled TF1 variant. Two-dimensional and three-dimensional homonuclear and heteronuclear NMR correlated spectra are analyzed and yield nearly complete assignments for the 1H and 15N resonances. Discrete protein secondary structure domains are also defined; in each monomer, three alpha-helices, an antiparallel beta-sheet, and an antiparallel beta-ribbon are identified. Analyses of two dimers formed from two distinct selectively deuteriated monomers serve to identify a number of interproton contacts as either intermonomeric or intramonomeric. An analysis of amide proton exchange reveals that the carboxy-terminal alpha-helix is less stable than the other two alpha-helices in each monomer. A previously proposed working structural model of the TF1 dimer [Geiduschek et al. (1990) J. Struct. Biol. 104, 84-90], based on the crystal structure of a highly homologous DBPII, the Bacillus stearothermophilus-encoded HU protein, is generally supported by our results. Several departures from this model, however, are noted. Most notably, the carboxy-terminal tail of TF1 adopts an alpha-helical conformation with a backbone distortion at Lys93.

Efficacy of albuterol administered by nebulizer versus spacer device in children with acute asthma.

The aim of this study was to compare the response to inhaled albuterol after administration by nebulizer with the response after administration by a metered-dose inhaler and spacer device (MDI-spacer) to children with acute asthma. In a double-blind fashion, 33 children (6 to 14 years of age) with forced expiratory volume in 1 second (FEV1) between 20% and 70% of predicted values, and who were seen in the emergency department with acute asthma, were studied. They were treated with aerosolized albuterol or placebo by MDI-spacer, followed immediately by albuterol or placebo administered by nebulizer with oxygen. The dose ratio for albuterol by MDI-spacer versus nebulizer was 1:5. Outcome measures included a clinical score, respiratory rate, arterial oxygen saturation, and FEV1, measured before and 10, 20, and 40 minutes after treatment. With the exception of heart rate (which increased in the nebulizer group and decreased in the MDI-spacer group (p < 0.05), no difference in the rate of improvement of clinical score, respiratory rate, arterial oxygen saturation, or FEV1 was noted during the 40-minute study period between children who received albuterol by nebulizer and those who received it by MDI-spacer. We conclude that spacers and nebulizers are equally effective means of delivering beta 2-agonists to children with acute asthma.

Using a sensory integrative approach to treat self-injurious behavior in an adult with profound mental retardation.

The treatment of self-injurious behavior in adults with mental retardation is a major challenge. A critical review of the literature compares sensory-based treatment studies by behavioral psychologists with sensory integrative treatment studies by occupational therapists. In general, therapists have used direct intervention in concentrated daily sessions. This report includes a single subject study that (a) demonstrates the clinical reasoning involved in the assessment and treatment planning process, (b) documents the efficacy of multiple short treatment sessions spread throughout the day, and (c) presents an alternative model of service provision in which direct care staff provide sensory and adaptive activities under the supervision of an occupational therapist. The use of sensory integration with adults with profound handicaps is presented as a valid application of a theory and treatment that was originally developed from work with higher functioning children with learning disabilities.

Advances in respiratory therapeutics in children.

A wide range of topics can be covered when considering a review of respiratory therapeutics. This review focuses on advances and controversies in the therapy of asthma, including issues regarding medications such as inhaled beta 2-agonists, inhaled corticosteroids, cromolyn sodium, and theophylline. Bronchodilator therapy for acute viral bronchiolitis remains a controversial issue and is discussed in light of recent published manuscripts. Issues regarding surfactant therapy for respiratory distress syndrome remain prominent in the neonatal respiratory therapeutics literature and recent findings in this area are reported. Advances in the treatment of cystic fibrosis, as well as a review concerning the pulmonary toxicity of various medications used in the treatment of pediatric illness are discussed.

A 1H-NMR study of the transcription factor 1 from Bacillus subtilis phage SPO1 by selective 2H-labeling. Complete assignment and structural analysis of the aromatic resonances for a 22-kDa homodimer.

1H-NMR experiments have been performed on transcription factor 1 (TF1) encoded by Bacillus subtilis phage SPO1. To study this 22-kDa homodimeric DNA-binding protein, a selective 2H-labeling strategy has been employed. Complete sequence-specific assignments of all the resonances from the five aromatic residues were determined by a modified standard sequential-assignment procedure. The reduced contribution of spin diffusion upon the long-mixing-time nuclear-Overhauser-enhancement spectroscopy for the selectively 2H-labeled variants, as opposed to the fully 1H-containing protein, has allowed for the identification of the spin systems and of the long-range dipolar contacts between Phe28 and Phe47 protons in the protein core and between Phe61 and Phe97 protons. The latter suggests an interaction between the proposed beta-ribbon DNA-binding arm and the carboxy terminus of the paired monomer. A previously proposed TF1 structural model [Geiduschek, E. P., Schneider, G. J. & Sayre, M. H. (1990) J. Struct. Biol. 104, 84-90)] has been modified using constrained-energy-minimization calculations incorporating the experimentally determined set of aromatic-to-aromatic contacts. This new model has been analyzed with regard to the relative mobility and the relative solvent accessibility of the aromatic residues which have been measured by the nonselective T1 relaxation times of the aromatic resonances for the fully 1H-containing protein and the relaxation time enhancements upon selective 2H-labeling, respectively.

Supervision of employees with moderate special needs.

A study was conducted to identify issues that confront workplace supervisors of people with learning disabilities (LD): problem behaviors, supervisory techniques, and the supervisor's needs. Conclusions are based on questionnaire responses from 65 supervisors in human service agencies and 27 interviews conducted with employers and supervisors in business and industry. Findings indicate that this special needs population surpasses the general population in exhibiting several positive work habits. Problem behaviors are most commonly addressed by establishing realistic performance standards, being flexible, and modifying tasks. Training supervisors who provide specific information concerning the individual are a major source of support to the on-site supervisor. Supervisors felt that personal commitment to this population and availability of specific information concerning LD were the most important influences on the quality of their work with the trainee. Findings from this study hold hope for the successful employment of people with LD.

Efficacy of adding nebulized ipratropium bromide to nebulized albuterol therapy in acute bronchiolitis.

Nebulized ipratropium bromide is though to be synergistic with albuterol in therapy for acute childhood asthma. Because the efficacy of ipratropium in bronchiolitis is uncertain and some infants with bronchiolitis do not respond to nebulized albuterol alone, the following study was undertaken. In this double-blind, placebo-controlled trial, 69 infants between 6 weeks and 24 months of age who exhibited the first episode of acute bronchiolitis were randomly assigned to receive either nebulized albuterol (0.15 mg/kg per dose) and ipratropium bromide (250 micrograms per dose) (group A, n = 36) or nebulized albuterol and normal saline (placebo) (group B, n = 33) for two doses, 1 hour apart. The two groups were comparable at baseline. Both therapies resulted in clinically significant improvement. However, the addition of ipratropium resulted in no additional benefit with respect to decrease in the respiratory rate (mean decreases 10.6/min vs decreases 8.6/min, P = .86), accessory muscle score (range 0 through 3) (decreases 0.92 vs decreases 0.82, z = -0.44), wheeze score (range 0 through 3) (decreases 0.94 vs 0.85, z = -0.20), oxygen saturation (increases 0.25% vs increases -0.33%, P = .86), or hospitalization rate (17 vs 10). The number of "nonresponders" and "clear responders" was also very similar in both groups. No toxicity was noted. The increase in heart rate was mild and similar in both groups (increases 6.7 vs increases 11.1). The power of the study to detect a difference between the two treatment groups in the respiratory rate change > or = 8/min is greater than 90%.(ABSTRACT TRUNCATED AT 250 WORDS)

Wheezing in infants with cystic fibrosis: clinical course, pulmonary function, and survival analysis.

Wheezing is a common finding in infants with cystic fibrosis (CF). This study was undertaken to determine the prevalence of wheezing in infants with CF and to compare the clinical outcome of those who wheezed in infancy with that of those who did not. The study cohort included 229 CF patients born between 1965 and 1979 with CF diagnosed before 2 years of age. Fifty-seven (25%) had physician-documented wheezing during the first 2 years of life. Wheezing had resolved by the age of 2 years in 50% of the patients and by the age of 4 years in 75%. Although wheezing seemed to be linked to a family history of allergy and asthma, the frequency of the delta F508 mutation was similar to that of the non-wheezers. There was no significant difference in survival at the age of 13 years between the two groups. At the age of 7 years, patients who had wheezed had significantly lower forced expiratory flow rate at mid-expiratory phase (85 +/- 34% predicted) compared with those with no wheezing history (101 +/- 34% predicted). At the age of 13 years, forced expiratory volume in 1 second values was lower in the wheezing group (69 +/- 24% predicted vs 78 +/- 21% predicted), as was forced expiratory flow rate at mid-expiratory phase (56 +/- 33% predicted vs 69 +/- 30% predicted). In conclusion, although wheezing in infants with CF seems to have diminished with age, pulmonary function abnormalities were more evident at 7 and 13 years of age in the group that wheezed than in the group that did not.