Assessing phylogenetic accuracy : a simulation study

A simulation model of phylogeny, called GENESIS, was developed to evaluate and to estimate the qualities of various numerical taxonomic procedures. The model produces sets of imaginary species with known character state distributions and with known phylogenies. The model can be made to produce these species and their phylogenies under different evolutionary conditions.Within GENESIS, there are two mathematical models that describe the diversification of the number of taxa. The number of taxa increases exponentially (the 'radiation' option), or according to a logistic curve (the 'equilibrium' option). As far as character evolution is concerned, GENESIS allows for two options; in the 'gradualistic' version character state changes occur in equal rates in the two daughter lineages after a speciation event; in the 'punctualistic' version these rates can be made to differ. Combining these options, GENESIS basically offers four evolutionary scenario's. The exact evolutionary conditions within each of these scenario's can be controlled by the user who must specify the values of a number of input parameters. GENESIS produces species and their phylogenies in the form of character data sets and corresponding true trees. The output is characterized by a number of tree statistics. Within each of the main evolutionary scenario's experiments were carried out, in which some input parameters were subjected to change while the others were kept constant. For the precise experimental design one is referred to the relevant paragraphs in chapters 4 - 6.A number of cladistic and phenetic tree making methods was evaluated. The PAUP, PHYLIP, Wagner78 and Hennig86 programs were used to produce most parsimonious trees. Group-compatibility was performed with CAFCA. Four UPGMA algorithms were used to construct phenograms: UPGMA using product squared euclidian distances of unstandardized characters (UPGMA-1); UPGMA using squared euclidian distances of unstandardized characters (UPGMA-2); UPGMA using product moment correlations of, unstandardized characters (UPGMA-3) and UPGMA using product moment correlations of standardized characters (UPGMA-4).Experiments using the most simple evolutionary scenario (combining the 'radiation' and 'gradualistic' options) showed that overall differences in accuracy were small between Wagner parsimony (PAUP, PHYLIP, Hennig86) and UPGMA-3. Parsimony with Wagner78, UPGMA-1, UPGMA-2, UPGMA-4 and especially compatibility analysis with CAFCA were shown to be inferior to these methods. The efficiency of various methods to recover the true tree, viz. Wagner78, PAUP, PHYLIP and CAFCA, depended on several tree properties, the consistency indices of both the true tree and the estimated tree being the most important ones.When more complicated evolutionary scenario's are considered, simulation experiments showed that UPGMA based on product moment correlations of unstandardized characters, clearly produced better results than the other phenetic or cladistic methods (Wagner78, Hennig86 and CAFCA). The efficiency now appeared to be affected most importantly by the stemminess of the true tree.A large number of phenetic procedures together with parsimony analysis, as performed with Hennig86 and Wagner78, were evaluated under a great variety of evolutionary conditions. McQuitty's similarity analysis and the average linkage method, both based on cosine- or product moment correlations of unstandardized characters, were found to perform consistently better that maximum parsimony and the other phenetic procedures.The average accuracy of UPGMA-3, over all experiments described in chapters 4 and 5, and as measured by the consensus fork index ( CFI ) was 0.76. Hennig86, PHYLIP (MIX) and PAUP produced similar results with an average CFI of 0.68. In chapter 6, the four superior phenetic methods (McQuitty's similarity analysis and the average linkage method, both based on cosine- or product moment correlations of unstandardized characters) had an average accuracy of 0.74. In these experiments accuracy of maximum parsimony as performed by Hennig86 was at 0.64. Also other authors generally observed equally low or even lower accuracy values (chapter 6).Stemminess and congruence of the characters with the tree as measured by the consistency index of the true tree, were found to be correlated with accuracy ( CFI ) in some experiments. Although, as also other authors pointed out, there may be a good correlation between an index and accuracy, there is the problem that the true tree must be known in order to compute the index. Therefore these indices cannot really be used as estimators of accuracy. Nevertheless they can serve to indicate the major determinants of accuracy. The consistency index of the estimated tree can be calculated in practice. Therefore the CI of the estimated tree might be used as a predictor of accuracy, though not a very reliable one. Estimated trees with low CI values, say less than 0.7, are probably not good estimates of the true tree.In the present study, overall low values of accuracy were obtained. This is in agreement with the findings of a number of other authors. All simulations in the this study were run to produce 20 'species'. If we use a cutoff point of CFI = 0.833, where 13 of the 18 subgroups would be correctly obtained, than it can safely be assumed that most published phylogenetic estimations are likely to be quite inaccurate. Therefore 1 support the view of authors that it is inappropriate to refer to phylogeny estimation methods as methods for phylogeny reconstruction.</em

Tackle your Tics:pilot findings of a brief, intensive group-based exposure therapy program for children with tic disorders

Tourette syndrome (TS) and other chronic tic disorders (CTD) are prevalent neurodevelopmental disorders, which can have a huge burden on families and society. Behavioral treatment is a first-line intervention for tic disorders. Despite demonstrated efficacy, tic reduction and utilization rates of behavioral treatment remain relatively low. Patient associations point to an urgent need for easy-to-undergo treatments that focus both on tic reduction and improvement of quality of life. To enhance treatment outcome and overcome treatment barriers, this pilot study's aim was to investigate the feasibility and preliminary results of a brief, intensive group-based treatment. Tackle your Tics is a 4-day intensive and comprehensive group-based program for children and adolescents (9-17 years) with a tic disorder, consisting of exposure and response prevention (ERP) treatment and additional supporting components, such as coping strategies, relaxing activities and parent support. Assessments were performed pre- and post-treatment and at 2 months follow-up, to test outcomes on tic severity and quality of life, and explore premonitory urges, emotional and behavioral functioning and treatment satisfaction (N = 14, of whom 13 completed the treatment). Parents and children rated this treatment positive on a treatment satisfaction questionnaire. On tic severity (Yale Global Tic Severity Scale) and quality of life (Gilles de la Tourette Syndrome Quality of Life Scale for children and adolescents), improvements between pre-treatment and follow-up were found. Intensive ERP in group format is promising as a feasible treatment to improve both tic severity as well as quality of life. Larger controlled trials are needed to establish its effectiveness

Targeted exhaled breath analysis for detection of Pseudomonas aeruginosa in cystic fibrosis patients

Background Pseudomonas aeruginosa (PA) is an important respiratory pathogen for cystic fibrosis (CF) patients. Routine microbiology surveillance is time-consuming, and is best performed on expectorated sputum. As alternative, volatile organic compounds (VOCs) may be indicative of PA colonisation. In this study, we aimed to identify VOCs associated with PA in literature and perform targeted exhaled breath analysis to recognize PA positive CF patients non-invasively. Methods This study consisted of 1) a literature review to select VOCs of interest, and 2) a cross-sectional CF study. Definitions used: A) PA positive, PA culture at visit/chronically; B) PA free, no PA culture in ≥12 months. Exhaled VOCs were identified via quadrupole MS. The primary endpoint was the area under the receiver operating characteristics curve (AUROCC) of individual VOCs as well as combined VOCs against PA culture. Results 241 VOCs were identified in literature, of which 56 were further evaluated, and 13 could be detected in exhaled breath in our cohort. Exhaled breath of 25 pediatric and 28 adult CF patients, PA positive (n=16) and free (n=28) was available. 3/13 VOCs were significantly (p<0.05) different between PA groups in children; none were in adults. Notably, a composite model based on 5 or 1 VOC(s) showed an AUROCC of 0.86 (CI 0.71–1.0) and 0.87 (CI 0.72–1.0) for adults and children, respectively. Conclusions Targeted VOC analysis appears to discriminate children and adults with and without PA positive cultures with clinically acceptable sensitivity values

Mechanisms of the noxious inflammatory cycle in cystic fibrosis

Multiple evidences indicate that inflammation is an event occurring prior to infection in patients with cystic fibrosis. The self-perpetuating inflammatory cycle may play a pathogenic part in this disease. The role of the NF-κB pathway in enhanced production of inflammatory mediators is well documented. The pathophysiologic mechanisms through which the intrinsic inflammatory response develops remain unclear. The unfolded mutated protein cystic fibrosis transmembrane conductance regulator (CFTRΔF508), accounting for this pathology, is retained in the endoplasmic reticulum (ER), induces a stress, and modifies calcium homeostasis. Furthermore, CFTR is implicated in the transport of glutathione, the major antioxidant element in cells. CFTR mutations can alter redox homeostasis and induce an oxidative stress. The disturbance of the redox balance may evoke NF-κB activation and, in addition, promote apoptosis. In this review, we examine the hypotheses of the integrated pathogenic processes leading to the intrinsic inflammatory response in cystic fibrosis

Key mechanisms governing resolution of lung inflammation

Innate immunity normally provides excellent defence against invading microorganisms. Acute inflammation is a form of innate immune defence and represents one of the primary responses to injury, infection and irritation, largely mediated by granulocyte effector cells such as neutrophils and eosinophils. Failure to remove an inflammatory stimulus (often resulting in failed resolution of inflammation) can lead to chronic inflammation resulting in tissue injury caused by high numbers of infiltrating activated granulocytes. Successful resolution of inflammation is dependent upon the removal of these cells. Under normal physiological conditions, apoptosis (programmed cell death) precedes phagocytic recognition and clearance of these cells by, for example, macrophages, dendritic and epithelial cells (a process known as efferocytosis). Inflammation contributes to immune defence within the respiratory mucosa (responsible for gas exchange) because lung epithelia are continuously exposed to a multiplicity of airborne pathogens, allergens and foreign particles. Failure to resolve inflammation within the respiratory mucosa is a major contributor of numerous lung diseases. This review will summarise the major mechanisms regulating lung inflammation, including key cellular interplays such as apoptotic cell clearance by alveolar macrophages and macrophage/neutrophil/epithelial cell interactions. The different acute and chronic inflammatory disease states caused by dysregulated/impaired resolution of lung inflammation will be discussed. Furthermore, the resolution of lung inflammation during neutrophil/eosinophil-dominant lung injury or enhanced resolution driven via pharmacological manipulation will also be considered