Inhaled nebulized adrenaline improves lung function in infants with acute bronchiolitis

Abstractβ2-agonists have questionable symptomatic effect in infants with acute bronchiolitis, whereas inhaled, nebulized racemic adrenaline, commonly used in Norway, appears (clinically) to be effective. Limited lung function observations during acute bronchiolitis exists, and less for assessing possible effects inhaled adrenaline.In this preliminary study, tidal flow-volume loops were measured in 16 infants with acute bronchiolitis and seven healthy controls (mean age 7·9 and 4·4 months, respectively), with repeated measurements 15 min after inhaled nebulized racemic adrenaline (4 mg diluted in 2 ml saline) in nine bronchiolitis patients.The ratio of time to reach peak tidal expiratory flow to total expiratory time (tPTEF/tE) was significantly reduced in children with acute bronchiolitis (mean, 95% CI) (0·08, 0·05–0·10) compared to controls (0·31, 0·18–0·43), with significant improvement after inhaled racemic adrenaline 0·19 (0·13–0·25), parallel with significant clinical improvement.Lung function (tPTEF/tE) was reduced in infants with acute bronchiolitis and improved significantly after inhaled racemic adrenaline. Inhaled racemic adrenaline is potentially an important alternative for treating infants with acute bronchiolitis

Lung function in children with Duchenne's muscular dystrophy

AbstractDuchenne's muscular dystrophy (DMD), characterized by gradually developing muscular weakness, leads to respiratory symptoms and reduced lung function. We aimed to assess lung function in 25 patients with DMD in relationship to age and muscular function. The 25 boys, mean age 13 years, comprized patients in southern Norway with DMD, taking part in an epidemiological follow-up study. None had chronic respiratory disease. Lung function was measured by maximum expiratory flow–volume loops and whole body plethysmography, and repeated after 1 year (n=14). Lung function was reduced compared to predicted values for healthy children. Forced expiratory volume in 1 sec (FEV1)% predicted and forced vital capacity (FVC)% predicted correlated (significantly) inversely to age. FEV1and FVC decreased annually 5·61 and 4·2% of predicted, respectively. Absolute values of FVC (litres) and FEV1(l sec−1) increased until mean age 14 years, decreasing thereafter. Values in % predicted decreased steadily throughout the age range (6–19 years). Lung function correlated closely to upper limb muscle function

Hyperactivation of NF-κB via the MEK signaling is indispensable for the inhibitory effect of cAMP on DNA damage-induced cell death

With cAMP signaling having a profound inhibitory effect on DNA damage-induced apoptosis in B-cell precursor acute lymphoblastic leukemia (BCP-ALL) cells, understanding how this signaling pathway affects the survival capacity of the cell has important implications for cancer therapy. We have recently shown that p53 is critical for the inhibitory effect of cAMP on genotoxic agents-mediated apoptosis in BCP-ALLs. Here, we show that elevation of cAMP levels in cells exposed to DNA damage enhances the nuclear translocation and DNA binding of NF-κB by accelerating the phosphorylation of IKKβ and thereby phosphorylation and degradation of IκBα. Furthermore, we show that the ability of cAMP to potentiate the ionizing radiation-induced activation of NF-κB requires the activity of MEK. Importantly, pharmacological or genetic ablation of NF-κB reversed the inhibitory effect of cAMP on DNA damage-induced apoptosis, demonstrating that, in addition to p53, cAMP relies on the activity of NF-κB to provide cells with a survival advantage in the face of DNA damage. Collectively, our results uncover a novel and important interaction between the cAMP and NF-κB pathways that may have implications for the targeted treatment of lymphoid malignancies, such as BCP-ALL, in which aberrant NF-κB activity functions as a driving force for treatment resistance

Analysis of Functional Differences between Hepatitis C Virus NS5A of Genotypes 1–7 in Infectious Cell Culture Systems

Hepatitis C virus (HCV) is an important cause of chronic liver disease. Several highly diverse HCV genotypes exist with potential key functional differences. The HCV NS5A protein was associated with response to interferon (IFN)-α based therapy, and is a primary target of currently developed directly-acting antiviral compounds. NS5A is important for replication and virus production, but has not been studied for most HCV genotypes. We studied the function of NS5A using infectious NS5A genotype 1–7 cell culture systems, and through reverse genetics demonstrated a universal importance of the amphipathic alpha-helix, domain I and II and the low-complexity sequence (LCS) I for HCV replication; the replicon-enhancing LCSI mutation S225P attenuated all genotypes. Mutation of conserved prolines in LCSII led to minor reductions in virus production for the JFH1(genotype 2a) NS5A recombinant, but had greater effects on other isolates; replication was highly attenuated for ED43(4a) and QC69(7a) recombinants. Deletion of the conserved residues 414-428 in domain III reduced virus production for most recombinants but not JFH1(2a). Reduced virus production was linked to attenuated replication in all cases, but ED43(4a) and SA13(5a) also displayed impaired particle assembly. Compared to the original H77C(1a) NS5A recombinant, the changes in LCSII and domain III reduced the amounts of NS5A present. For H77C(1a) and TN(1a) NS5A recombinants, we observed a genetic linkage between NS5A and p7, since introduced changes in NS5A led to changes in p7 and vice versa. Finally, NS5A function depended on genotype-specific residues in domain I, as changing genotype 2a-specific residues to genotype 1a sequence and vice versa led to highly attenuated mutants. In conclusion, this study identified NS5A genetic elements essential for all major HCV genotypes in infectious cell culture systems. Genotype- or isolate- specific NS5A functional differences were identified, which will be important for understanding of HCV NS5A function and therapeutic targeting

Long-Term Gynecological Outcomes in Women with Congenital Adrenal Hyperplasia due to 21-Hydroxylase Deficiency

Background. Our knowledge on long-term outcome in CAH remains incomplete. Methods. In a prospective study (33 CAH patients, 33 age-matched controls), reproductive outcomes, self-rating of genital appearance and function, and sexuality were correlated to degree of initial virilisation, genotype, and surgery. Results. Patients had larger median clitoral lengths (10.0 mm [range 2–30] versus 3.5 [2–8], P < .001), shorter vaginal length (121 mm [100–155] versus 128 [112–153], P = .12), lower uterine volumes (29.1 ml [7.5–56.7] versus 47.4 [15.9–177.5], P = .009), and higher ovarian volumes (4.4 ml [1.3–10.8] versus 2.8 [0.6–10.8], P = .09) than controls. Satisfaction with genital appearance was lower and negatively correlated to degree of initial virilisation (rs = ≤−0.39, P ≤ .05). More patients had never had intercourse (P = .001), and age at 1st intercourse was higher (18 yrs versus 16 yrs, P = .02). Conclusion. Despite overall acceptable cosmetic results, reproductive outcomes were suboptimal, supporting that multidisciplinary teams should be involved in adult follow up of CAH patients

Guidelines; from foe to friend? Comparative interviews with GPs in Norway and Denmark

<p>Abstract</p> <p>Background</p> <p>GPs follow clinical guidelines to varying degrees across practices, regions and countries, but a review study of GPs' attitudes to guidelines found no systematic variation in attitudes between studies from different countries. However, earlier qualitative studies on this topic are not necessarily comparable. Hence, there is a lack of empirical comparative studies of GP's attitudes to following clinical guidelines. In this study we reproduce a Norwegian focus group study of GPs' general attitudes to national clinical guidelines in Denmark and conduct a comparative analysis of the findings.</p> <p>Methods</p> <p>A strategic sample of GP's in Norway (27 GPs) and Denmark (18 GPs) was interviewed about their attitudes to guidelines, and the interviews coded and compared for common themes and differences.</p> <p>Results</p> <p>Similarities dominated the comparative material, but the analysis also revealed notable differences in attitudes between Norwegian and the Danish GPs. The most important difference was related to GP's attitudes to clinical guidelines that incorporated economic evaluations. While the Norwegian GPs were sceptical to guidelines that incorporated economic evaluation, the Danish GPs regarded these guidelines as important and legitimate. We suggest that the differences could be explained by the history of guideline development in Norway and Denmark respectively. Whereas government guidelines for rationing services were only newly introduced in Norway, they have been used in Denmark for many years.</p> <p>Conclusion</p> <p>Comparative qualitative studies of GPs attitudes to clinical guidelines may reveal cross-national differences relating to the varying histories of guideline development. Further studies are needed to explore this hypothesis.</p