Simultaneous improvement of grain yield and protein content in durum wheat by different phenotypic indices and genomic selection.

KEY MESSAGE: Simultaneous improvement of protein content and grain yield by index selection is possible but its efficiency largely depends on the weighting of the single traits. The genetic architecture of these indices is similar to that of the primary traits. Grain yield and protein content are of major importance in durum wheat breeding, but their negative correlation has hampered their simultaneous improvement. To account for this in wheat breeding, the grain protein deviation (GPD) and the protein yield were proposed as targets for selection. The aim of this work was to investigate the potential of different indices to simultaneously improve grain yield and protein content in durum wheat and to evaluate their genetic architecture towards genomics-assisted breeding. To this end, we investigated two different durum wheat panels comprising 159 and 189 genotypes, which were tested in multiple field locations across Europe and genotyped by a genotyping-by-sequencing approach. The phenotypic analyses revealed significant genetic variances for all traits and heritabilities of the phenotypic indices that were in a similar range as those of grain yield and protein content. The GPD showed a high and positive correlation with protein content, whereas protein yield was highly and positively correlated with grain yield. Thus, selecting for a high GPD would mainly increase the protein content whereas a selection based on protein yield would mainly improve grain yield, but a combination of both indices allows to balance this selection. The genome-wide association mapping revealed a complex genetic architecture for all traits with most QTL having small effects and being detected only in one germplasm set, thus limiting the potential of marker-assisted selection for trait improvement. By contrast, genome-wide prediction appeared promising but its performance strongly depends on the relatedness between training and prediction sets.

Prophylactic use of colchicine in preventing radiation induced coronary artery disease.

Radiation therapy is one of the primary treatments in fighting breast cancer, one of the most common cancers in the US. One of the dose limiting factors of this therapy is radiation induced heart damage that results from mediastinal radiation. Recently statins, a medication typically used to lower cholesterol levels, have been suggested as a prophylactic treatment to potentially mitigate this process. Similarly, we hypothesized whether colchicine, an anti-inflammatory medication that is presently used in the treatment of gout and pericarditis, might be used to prevent coronary artery disease induced by radiation therapy. We hypothesize that colchicine may help prevent the deleterious effect on coronary arteries induced by radiation therapy by inhibiting inflammation and platelet aggregation. The pathophysiology of radiation induced coronary artery disease is similar to that of coronary artery disease in the general population. Inflammation, fibrosis and platelet aggregation play a key role in this process. After radiation therapy, inflammation occurs, recruiting leukocytes, particularly neutrophils and monocytes. Neutrophils are fibrotic mediators, and macrophages form foam cells in the intimal layer of the vessel wall, leading to the build-up of atherosclerotic plaques. Platelet aggregation, both initially and upon plaque rupture, is also a culprit in exacerbating radiation damage. Colchicine is known to inhibit microtubule polymerization and therefore inhibits mitosis, neutrophil motility and has been shown to decrease platelet aggregation. Its anti-inflammatory properties have been attributed to several different effects based on microtubule dysfunction. Colchicine has also been shown to affect the expression of adhesion molecules on endothelial cells, leukocytes, and to decrease activation of thrombin induced platelet aggregation. There is evidence to suggest that colchicine may be beneficial in the treatment of radiation induced coronary artery disease due to its anti-inflammatory and anti-coagulant properties. This idea would be beneficial for future studies.

Microvolt T-wave alternans in patients undergoing elective coronary artery bypass grafting: a pilot study.

INTRODUCTION: We designed a prospective observational study targeting a selective population of patients undergoing elective coronary artery bypass grafting with normal systolic function. In this study we looked at the prevalence of pre-operative microvolt T-wave alternans and if it predicts atrial fibrillation after surgery. METHODS: The inclusion criteria included all patients referred to the cardiothoracic outpatient clinic for elective bypass, who can perform aerobic exercise, with a recent exercise stress test exercising at least to 85% of the maximal predicted heart rate (220 - age) and with non-limiting chest pain at maximal exercise. Twenty patients met the inclusion/exclusion criteria between May 2008 and February 2010. The hospital course of those patients was followed, and in-hospital events were recorded. RESULTS: Nine out twenty (45%) of patients had a non-negative microvolt T-wave alternans tracing. Six patients (30%) developed new onset atrial fibrillation post surgery. Patients with non-negative microvolt level T-wave alternans are more likely to develop atrial fibrillation post coronary artery bypass grafting then patients with negative microvolt level T-wave alternans (p=0.05). CONCLUSIONS: This pilot study provides the first clinical evidence that patients with ischemic heart disease and normal systolic function have a high prevalence of abnormal microvolt T-wave alternans and might be at higher risk of sudden cardiac death. In addition our results show that microvolt level T-wave alternans predicts post coronary artery bypass grafting new onset atrial fibrillation.

Effects of a FLAP inhibitor, GSK2190915, in asthmatics with high sputum neutrophils.

Patients with refractory asthma frequently have neutrophilic airway inflammation and respond poorly to inhaled corticosteroids. This study evaluated the effects of an oral 5-lipoxygenase-activating protein (FLAP) inhibitor, GSK2190915, in patients with asthma and elevated sputum neutrophils. Patients received 14 (range 13-16) days treatment with GSK2190915 100 mg and placebo with a minimum 14 day washout in a double-blind, cross-over, randomised design (N = 14). Sputum induction was performed twice pre-dose in each treatment period to confirm sputum neutrophilia, and twice at the end of each treatment period. The primary endpoint was the percentage and absolute sputum neutrophil count, averaged for end-of-treatment visits. GSK2190915 did not significantly reduce mean percentage sputum neutrophils (GSK2190915-placebo difference [95% CI]: -0.9 [-12.0, 10.3]), or mean sputum neutrophil counts (GSK2190915/placebo ratio [95% CI]: 1.06 [0.43, 2.61]). GSK2190915 resulted in a marked suppression (>90%) of sputum LTB4 and urine LTE4, but did not alter clinical endpoints. There were no safety issues. Despite suppressing the target mediator LTB4, FLAP inhibitor GSK2190915 had no short-term effect on sputum cell counts or clinical endpoints in patients with asthma and sputum neutrophilia.

Peripheral blood dendritic cell subtypes are significantly elevated in subjects with asthma.

BACKGROUND: Dendritic cells (DCs) are crucial for the processing of antigens, T lymphocyte priming and the development of asthma and allergy. Smokers with asthma display altered therapeutic behaviour and a reduction in endobronchial DC CD83 expression compared with non-smokers with asthma. No information is available on the impact of smoking on peripheral blood DC profiles. OBJECTIVE: Determine peripheral blood DC profiles in subjects with and without asthma with differing smoking histories. METHODS: Forty-three asthmatics (17 smokers, nine ex-smokers and 17 never-smokers) and 16 healthy volunteers (nine smokers and seven never-smokers) were recruited. Spirometry, exhaled nitric oxide and venesection was performed. DC elution was by flow cytometry via the expression of DC surface markers [plasmacytoid (pDC) (BDCA-2, CD303), type 1 conventional (cDC) (BDCA-1, CD1c), and type 2 cDC (BDCA-3, CD141)]. RESULTS: Subjects with asthma displayed increases in all DC subtypes compared with normal never-smokers: [type 1 cDCs - asthma [median% (IQR)]: 0.59% (0.41, 0.74), normal never-smokers: 0.35% (0.26, 0.43), P=0.013]; type 2 cDCs - asthma: 0.04% (0.02, 0.06), normal never-smokers: 0.02% (0.01, 0.03), P=0.008 and pDCs - asthma: 0.32% (0.27, 0.46), normal never-smokers: 0.22% (0.17, 0.31), P=0.043, and increased pDC and type 1 cDCs compared with normal smokers. Smoking did not affect DC proportions in asthma. Cigarette smoking reduced pDC proportions in normal subjects [normal never-smokers: 0.22% (0.17, 0.31); normal smokers: 0.09% (0.08, 0.15), P=0.003]. CONCLUSIONS AND CLINICAL RELEVANCE: This study shows for the first time that subjects with asthma display a large increase in peripheral blood DC proportions. Cigarette smoking in asthma did not affect the peripheral blood DC profile but did suppress pDC proportions in non-asthmatic subjects. Asthma is associated with a significant increase in circulating DCs, reflecting increased endobronchial levels and the importance of DCs to the development and maintenance of asthma. (Clinical trials.gov identifier: NCT00411320)

Bronchodilatory effect of the PPAR-gamma agonist rosiglitazone in smokers with asthma.

Smokers with asthma show a reduced response to inhaled corticosteroids. We hypothesized that a peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonist would be superior for the clinical treatment of these asthma patients. Forty-six smokers with asthma were randomized to inhaled beclometasone dipropionate (200 microg per day) or rosiglitazone (8 mg per day) for 4 weeks. Rosiglitazone produced improvements in lung function (forced expiratory volume in 1 s (FEV(1)) = 183 ml, P = 0.051; forced expiratory flow between 25 and 75% of the forced vital capacity (FEF(25-75)) = 0.24 l/s, P = 0.030) as compared with inhaled beclometasone dipropionate. Further trials using PPAR-gamma agonists in steroid-resistant airway disease are indicated.

Effect of low-dose theophylline plus beclometasone on lung function in smokers with asthma: a pilot study.

Smoking is common in asthma and is associated with worse asthma control and a reduced therapeutic response to corticosteroids. The present authors hypothesised that treating smokers with asthma with low-dose theophylline added to inhaled corticosteroids would enhance steroid sensitivity and thereby improve lung function and symptoms. In a double-blind, parallel group exploratory trial, 68 asthmatic smokers were randomised to one of three treatments for 4 weeks: inhaled beclometasone (200 microg day(-1)), theophylline (400 mg day(-1)) or both treatments combined. Outcome measures included change in lung function and Asthma Control Questionnaire (ACQ) scores. At 4 weeks, theophylline added to inhaled beclometasone produced an improvement in peak expiratory flow (39.9 L min(-1), 95% confidence intervals (CI) 10.9-68.8) and ACQ score (-0.47, 95% CI -0.91- -0.04) and a borderline improvement in pre-bronchodilator forced expiratory volume in one second (mean difference 165 mL, 95% CI -13-342) relative to inhaled corticosteroid alone. Theophylline alone improved the ACQ score (-0.55, 95% CI -0.99- -0.11), but not lung function. In the present pilot study, the combination of low-dose theophylline and inhaled beclometasone produced improvements in both lung function and symptoms in a group of smokers with asthma. Larger trials are required to extend and confirm these findings.

Effects of atorvastatin added to inhaled corticosteroids on lung function and sputum cell counts in atopic asthma.

BACKGROUND: Statins have anti-inflammatory properties that may be beneficial in the treatment of asthma. A study was undertaken to test the hypothesis that atorvastatin added to inhaled corticosteroids improves lung function and airway inflammation in atopic adults with asthma. METHODS: 54 adults with atopic asthma were recruited to a double-blind randomised controlled crossover trial comparing the effect of oral atorvastatin 40 mg daily with that of a matched placebo on asthma control and airway inflammation. Each treatment was administered for 8 weeks separated by a 6-week washout period. The primary outcome was morning peak expiratory flow (PEF). Secondary outcomes included forced expiratory volume in 1 s, asthma control questionnaire score, airway hyper-responsiveness to methacholine, induced sputum cytology and inflammatory biomarkers. RESULTS: At 8 weeks the change in mean morning PEF compared with baseline did not differ substantially between the atorvastatin and placebo treatment periods (mean difference -0.5 l/min, 95% CI -10.6 to 9.6, p = 0.921). Values for other clinical outcomes were similar between the atorvastatin and placebo treatment periods. The absolute sputum macrophage count was reduced after atorvastatin compared with placebo (mean difference -45.0 x 10(4) cells, 95% CI -80.1 to -9.7, p = 0.029), as was the sputum fluid leucotriene B4 (mean difference -88.1 pg/ml, 95% CI -156.4 to -19.9, p = 0.014). CONCLUSION: The addition of atorvastatin to inhaled corticosteroids results in no short-term improvement in asthma control but reduces sputum macrophage counts in mild to moderate atopic asthma. The change in sputum macrophage count suggests potential areas for investigation of statins in other chronic lung diseases.

Role of symptoms and lung function in determining asthma control in smokers with asthma.

BACKGROUND: Cigarette smoking in asthma increases the severity and accelerates the decline in lung function. The relative role of symptoms and lung function in determining asthma control in smokers with asthma is not known. AIM OF THE STUDY: The aim of this study was to compare asthma control in smokers vs never-smokers with asthma, using the validated Juniper asthma control questionnaire (ACQ), and assess if any difference was because of a particular symptom or the forced expiratory volume in one second (FEV(1)) value. METHODS: This was a cross-sectional study of 134 asthmatics (74 never-smokers and 60 smokers) with >or=15% reversibility in FEV(1) after salbutamol. All subjects completed the ACQ, recording FEV(1) and asthma symptoms (night awakening, morning symptoms, dyspnoea, wheeze, activity limitation and use of reliever inhaler). RESULTS: Compared with the never-smokers, smokers with asthma had significantly worse median (IQR) total asthma control score [1.6 (1.1-2.3) vs 2.8 (1.7-3.4); (P < 0.0001)] and in each of the six individual symptom question scores (P < 0.001), but no difference in FEV(1) levels (P = 0.908). CONCLUSION: Asthma control is significantly worse in asthmatics who smoke compared with never-smokers, with all symptoms related to asthma control uniformly worse in smokers, independent of FEV(1).

Hb H hydrops foetalis syndrome: a case report and review of literature.

Haemoglobin H (Hb H) disease is caused by deletion or inactivation of three alpha-globin genes, leaving only one intact and active alpha-globin gene. People with Hb H disease usually have moderate anaemia, but are generally thought to be asymptomatic. Some Hb H disease patients require transfusions, and there are reports of fetuses with Hb H disease who have severe anaemia in utero resulting in fatal hydrops foetalis syndrome. We now report a case of Hb H hydrops foetalis syndrome, caused by the inheritance of a hitherto novel alpha-globin gene point mutation (codon 35 TCC-->CCC or Serine-->Proline) and an alpha-thalassaemia deletion of the Filipino type removing all zeta-alpha-globin genes on the other chromosome 16. The infant was delivered prematurely because of pericardial effusion and fetal distress, and was found to have severe anaemia and congenital anomalies. A review of the relevant literature on this syndrome is presented, and serves to underscore the phenotypic variations of Hb H disease and the need for surveillance for this condition among newborns and genetic counselling in communities with a high proportion of at-risk populations.

Laboratory screening prior to ECT.

INTRODUCTION: Screening for occult disease using laboratory testing prior to electroconvulsive therapy (ECT) is a common practice with little empirical support. METHOD: In a pre-ECT and post-ECT sample of 73 and 562 (respectively) patients evaluated for ECT, the utility of the electrocardiogram, serum sodium, serum potassium, serum creatinine, chest radiograph, hemoglobin level, and white blood cell count was examined. RESULTS AND DISCUSSION: Reviewing the electrocardiogram and measuring sodium and potassium levels prior to the administration of ECT appear to be useful screening tests because they detect correctable unexpected conditions that are relevant to the risk of the procedure. Hemoglobin and white blood cell count abnormalities did not influence the administration of ECT or predict ECT complications. An abnormal creatinine level or abnormal chest radiograph prior to the administration of ECT predicted a poor medical prognosis that appeared largely unrelated to the administration of ECT.

How much work is required to puncture dura with Tuohy needles?

The effects of needle bevel orientation and cerebrospinal fluid (CSF) pressure on dural displacement and force required to penetrate cadaveric dura were studied using 40 samples. A constant hydrostatic pressure was applied to the subdural surface, either high or low, simulating the sitting and lateral positions. A 17-gauge Tuohy needle was advanced through the dura with the bevel oriented parallel or perpendicular to dural fibres. Travel distance and peak force at which dural penetration occurred were measured under both pressure conditions. The work required to produce dural penetration was calculated. Greater force and work were required to penetrate dura in the perpendicular orientation (P < 0.05), regardless of the subdural pressure exerted. Dural displacement was similar under both pressure conditions.

An algorithm to aid in the investigation of thalassemia trait in multicultural populations.

CONTEXT: The differentiation between iron deficiency and a thalassemia syndrome is an important consideration in the investigation of microcytic anemia. OBJECTIVE: An established statistical method was used to demonstrate the importance of considering ethnic background in combination with mean cell volume (MCV) in the investigation of beta-thalassemia trait in a multicultural urban population. DESIGN: Posttest probabilities for beta-thalassemia trait were calculated using likelihood ratios for various microcytic MCV ranges in conjunction with published pretest probabilities for beta-thalassemia trait based on ethnic background. SETTING: Regional hemoglobinopathy laboratory, St Joseph's Hospital, Hamilton, Ontario, Canada. PATIENTS: Patient data were derived from a previously published study. The original study cohort consisted of 789 patients aged 18 years or older who had an MCV less than 80 fL and were referred for routine complete blood count during a 6-month period. MAIN OUTCOME MEASURES: Posttest probabilities. RESULTS: Simplified tables for the determination of posttest probabilities for beta-thalassemia trait in individual patients based on ethnic background and MCV are provided. An algorithm to assist in determining when thalassemia investigations are indicated is presented. CONCLUSIONS: A high index of suspicion based on ethnic background and low MCV can provide increased sensitivity and specificity for the detection of thalassemia trait in centers with multicultural populations similar to the study population.

A reliable screening test to identify adult carriers of the (--SEA) alpha zero-thalassemia deletion. Detection of embryonic zeta-globin chains by enzyme-linked immunosorbent assay.

Homozygous (--SEA) alpha zero-thalassemia deletion, the cause of up to 80% of fetal hydrops in Southeast Asia, is encountered in many other countries. Heterozygous carrier rates of the deletion in Southeast Asian populations range from 4% to 14%. The laboratory screening for adult carriers of (--SEA) and other alpha zero-thalassemia deletions currently rests primarily with microscopic detection of hemoglobin H inclusion bodies within erythrocytes (Hb H screen). This test is laborious and observer dependent and has poor sensitivity. We assessed a colorimetric enzyme-linked immunosorbent assay (ELISA) to detect embryonic zeta-globin chains in adult hemolysates as an alternative to detect (--SEA) alpha zero-thalassemia deletion carriers. Blood samples from 221 adults with a mean corpuscular volume less than 80 micron 3 (80 fL) were studied prospectively by currently accepted hemoglobin screening tests and ELISA. Suspected cases of alpha-thalassemia were confirmed by DNA-based diagnostics. ELISA was highly sensitive (1.0) and specific (0.94) for the detection of adult carriers of (--SEA) alpha zero-thalassemia deletion. The hemoglobin H screen had a sensitivity of 0.47 and specificity of 0.99. The zeta-globin ELISA proved simple to perform, rapid, and applicable to high volume or population-based screening programs.

Effect of hemodialysis on the signal-averaged electrocardiogram.

The presence of late potentials (LPs) on signal-averaged electrocardiography (SAECG) is predictive of ventricular tachycardia. The effect of hemodialysis (HD) on SAECG has not been well studied. SAECG was evaluated in 28 patients with chronic renal failure immediately before and after HD. In each SAECG, QRS duration, low-amplitude signal duration (LASd), and root-mean-square voltage of the terminal 40 milliseconds of the QRS (RMS40) were measured. To evaluate the effect of fluid removal on SAECG, the last 12 patients were studied during two different HD sessions, one with and one without fluid removal. Two-dimensional echocardiography was performed before and after HD on these 12 patients. At baseline, four patients met the criteria for LPs on SAECG. Only one patient met the criteria for LPs on SAECG after HD. After HD, the mean LASd decreased (28.3 +/- 12.9 to 24.9 +/- 10.1 milliseconds; P = 0.041) and RMS40 increased (63.0 +/- 56.9 to 79.0 +/- 59.2 microV; P = 0. 006). Among the 12 patients who underwent HD with and without fluid removal, left ventricular end-diastolic dimension decreased with (5. 4 +/- 0.6 to 5.1 +/- 0.6 cm; P = 0.024) but not without fluid removal (5.2 +/- 0.3 to 5.1 +/- 0.4 cm; P = not significant [NS]). RMS40 improved with (43.8 +/- 23.1 to 53.2 +/- 22.6 microV; P = 0. 03) but not without fluid removal (51.0 +/- 26.5 to 51.5 +/- 24.2 microV; P = NS). A significant negative correlation was found between change in body weight and change in RMS40 parameter (r = 0. 456; P = 0.0381). SAECG parameters are abnormal in a significant proportion of patients with chronic renal failure and improve with HD despite electrolyte and other proarrhythmic changes. Decreased left ventricular dimension because of fluid removal during HD is one possible explanation for this improvement.