Respiratory Exacerbations in Indigenous Children From Two Countries With Non-Cystic Fibrosis Chronic Suppurative Lung Disease/Bronchiectasis

BACKGROUND: Acute respiratory exacerbations (AREs) cause morbidity and lung function decline in children with chronic suppurative lung disease (CSLD) and bronchiectasis. In a prospective longitudinal cohort study, we determined the patterns of AREs and factors related to increased risks for AREs in children with CSLD/bronchiectasis. METHODS: Ninety-three indigenous children aged 0.5 to 8 years with CSLD/bronchiectasis in Australia (n = 57) and Alaska (n = 36) during 2004 to 2009 were followed for > 3 years. Standardized parent interviews, physical examinations, and medical record reviews were undertaken at enrollment and every 3 to 6 months thereafter. RESULTS: Ninety-three children experienced 280 AREs (median = 2, range = 0-11 per child) during the 3-year period; 91 (32%) were associated with pneumonia, and 43 (15%) resulted in hospitalization. Of the 93 children, 69 (74%) experienced more than two AREs over the 3-year period, and 28 (30%) had more than one ARE in each study year. The frequency of AREs declined significantly over each year of follow-up. Factors associated with recurrent (two or more) AREs included age < 3 years, ARE-related hospitalization in the first year of life, and pneumonia or hospitalization for ARE in the year preceding enrollment. Factors associated with hospitalizations for AREs in the first year of study included age < 3 years, female caregiver education, and regular use of bronchodilators. CONCLUSIONS: AREs are common in children with CSLD/bronchiectasis, but with clinical care and time AREs occur less frequently. All children with CSLD/bronchiectasis require comprehensive care; however, treatment strategies may differ for these patients based on their changing risks for AREs during each year of care.

Comparative genomic analysis of human Chlamydia pneumoniae isolates from respiratory, brain and cardiac tissues

Chlamydia pneumoniae is an obligate intracellular bacterium implicated in a wide range of human diseases including atherosclerosis and Alzheimer's disease. Efforts to understand the relationships between C. pneumoniae detected in these diseases have been hindered by the availability of sequence data for non-respiratory strains. In this study, we sequenced the whole genomes for C. pneumoniae isolates from atherosclerosis and Alzheimer's disease, and compared these to previously published C. pneumoniae genomes. Phylogenetic analyses of these new C. pneumoniae strains indicate two sub-groups within human C. pneumoniae, and suggest that both recombination and mutation events have driven the evolution of human C. pneumoniae. Further fine-detailed analyses of these new C. pneumoniae sequences show several genetically variable loci. This suggests that similar strains of C. pneumoniae are found in the brain, lungs and cardiovascular system and that only minor genetic differences may contribute to the adaptation of particular strains in human disease.

Deriving optimal fishing effort for managing Australia's Moreton Bay multispecies trawl fishery with aggregated effort data

Deriving an estimate of optimal fishing effort or even an approximate estimate is very valuable for managing fisheries with multiple target species. The most challenging task associated with this is allocating effort to individual species when only the total effort is recorded. Spatial information on the distribution of each species within a fishery can be used to justify the allocations, but often such information is not available. To determine the long-term overall effort required to achieve maximum sustainable yield (MSY) and maximum economic yield (MEY), we consider three methods for allocating effort: (i) optimal allocation, which optimally allocates effort among target species; (ii) fixed proportions, which chooses proportions based on past catch data; and (iii) economic allocation, which splits effort based on the expected catch value of each species. Determining the overall fishing effort required to achieve these management objectives is a maximizing problem subject to constraints due to economic and social considerations. We illustrated the approaches using a case study of the Moreton Bay Prawn Trawl Fishery in Queensland (Australia). The results were consistent across the three methods. Importantly, our analysis demonstrated the optimal total effort was very sensitive to daily fishing costs-the effort ranged from 9500-11 500 to 6000-7000, 4000 and 2500 boat-days, using daily cost estimates of $0, $500, $750, and $950, respectively. The zero daily cost corresponds to the MSY, while a daily cost of $750 most closely represents the actual present fishing cost. Given the recent debate on which costs should be factored into the analyses for deriving MEY, our findings highlight the importance of including an appropriate cost function for practical management advice. The approaches developed here could be applied to other multispecies fisheries where only aggregated fishing effort data are recorded, as the literature on this type of modelling is sparse.

Effects of fish density distribution and effort distribution on catchability

The effects of fish density distribution and effort distribution on the overall catchability coefficient are examined. Emphasis is also on how aggregation and effort distribution interact to affect overall catch rate [catch per unit effort (cpue)]. In particular, it is proposed to evaluate three indices, the catchability index, the knowledge parameter, and the aggregation index, to describe the effectiveness of targeting and the effects on overall catchability in the stock area. Analytical expressions are provided so that these indices can easily be calculated. The average of the cpue calculated from small units where fishing is random is a better index for measuring the stock abundance. The overall cpue, the ratio of lumped catch and effort, together with the average cpue, can be used to assess the effectiveness of targeting. The proposed methods are applied to the commercial catch and effort data from the Australian northern prawn fishery. The indices are obtained assuming a power law for the effort distribution as an approximation of targeting during the fishing operation. Targeting increased catchability in some areas by 10%, which may have important implications on management advice.

Analysing commercial catch and effort data from a penaeid trawl fishery: A comparison of linear models, mixed models, and generalised estimating equations approaches

Statistical methods are often used to analyse commercial catch and effort data to provide standardised fishing effort and/or a relative index of fish abundance for input into stock assessment models. Achieving reliable results has proved difficult in Australia's Northern Prawn Fishery (NPF), due to a combination of such factors as the biological characteristics of the animals, some aspects of the fleet dynamics, and the changes in fishing technology. For this set of data, we compared four modelling approaches (linear models, mixed models, generalised estimating equations, and generalised linear models) with respect to the outcomes of the standardised fishing effort or the relative index of abundance. We also varied the number and form of vessel covariates in the models. Within a subset of data from this fishery, modelling correlation structures did not alter the conclusions from simpler statistical models. The random-effects models also yielded similar results. This is because the estimators are all consistent even if the correlation structure is mis-specified, and the data set is very large. However, the standard errors from different models differed, suggesting that different methods have different statistical efficiency. We suggest that there is value in modelling the variance function and the correlation structure, to make valid and efficient statistical inferences and gain insight into the data. We found that fishing power was separable from the indices of prawn abundance only when we offset the impact of vessel characteristics at assumed values from external sources. This may be due to the large degree of confounding within the data, and the extreme temporal changes in certain aspects of individual vessels, the fleet and the fleet dynamics.

A maximum-likelihood method for estimating natural mortality and catchability coefficient from catch-and-effort data

A simple stochastic model of a fish population subject to natural and fishing mortalities is described. The fishing effort is assumed to vary over different periods but to be constant within each period. A maximum-likelihood approach is developed for estimating natural mortality (M) and the catchability coefficient (q) simultaneously from catch-and-effort data. If there is not enough contrast in the data to provide reliable estimates of both M and q, as is often the case in practice, the method can be used to obtain the best possible values of q for a range of possible values of M. These techniques are illustrated with tiger prawn (Penaeus semisulcatus) data from the Northern Prawn Fishery of Australia.

Strengthening Incentives for Student Effort and Learning: Michigan’s Merit Award Program?

[Excerpt] One of the primary reasons American students learn a good deal less during secondary school than students in other industrialized nations is that they devote less time and intellectual energy to the task.1 Accountability systems designed to get teachers to try harder and set higher standards will not produce more student learning if [as one high school teacher put it] “students are sitting back in their desks, arms crossed, waiting for their teachers to make them smart (Zoch, 1998, p. 70).” Learning is not a passive act; it requires the time and active involvement of the learner. In a classroom with 1 teacher and 25 students, there are 25 learning hours spent for every hour of teaching time. Learning takes work and that work is generally not going to be as much fun as hanging out with friends or watching TV. If students cannot be motivated to give up some time socializing or watching TV so that they can learn difficult material and develop high level skills, the time and talents of teachers will be wasted.

Mitochondrial Malfunction in Tumor Formation and Neuromuscular Diseases : Consequences of defects in fumarate hydratase and in the respiratory chain

The mitochondrion is an organelle of outmost importance, and the mitochondrial network performs an array of functions that go well beyond ATP synthesis. Defects in mitochondrial performance lead to diseases, often affecting nervous system and muscle. Although many of these mitochondrial diseases have been linked to defects in specific genes, the molecular mechanisms underlying the pathologies remain unclear. The work in this thesis aims to determine how defects in mitochondria are communicated within - and interpreted by - the cells, and how this contributes to disease phenotypes. Fumarate hydratase (FH) is an enzyme of the citrate cycle. Recessive defects in FH lead to infantile mitochondrial encephalopathies, while dominant mutations predispose to tumor formation. Defects in succinate dehydrogenase (SDH), the enzyme that precedes FH in the citrate cycle, have also been described. Mutations in SDH subunits SDHB, SDHC and SDHD are associated with tumor predisposition, while mutations in SDHA lead to a characteristic mitochondrial encephalopathy of childhood. Thus, the citrate cycle, via FH and SDH, seems to have essential roles in mitochondrial function, as well as in the regulation of processes such as cell proliferation, differentiation or death. Tumor predisposition is not a typical feature of mitochondrial energy deficiency diseases. However, defects in citrate cycle enzymes also affect mitochondrial energy metabolism. It is therefore necessary to distinguish what is specific for defects in citrate cycle, and thus possibly associated with the tumor phenotype, from the generic consequences of defects in mitochondrial aerobic metabolism. We used primary fibroblasts from patients with recessive FH defects to study the cellular consequences of FH-deficiency (FH-). Similarly to the tumors observed in FH- patients, these fibroblasts have very low FH activity. The use of primary cells has the advantage that they are diploid, in contrast with the aneuploid tumor cells, thereby enabling the study of the early consequences of FH- in diploid background, before tumorigenesis and aneuploidy. To distinguish the specific consequences of FH- from typical consequences of defects in mitochondrial aerobic metabolism, we used primary fibroblasts from patients with MELAS (mitochondrial encephalopathy with lactic acidosis and stroke-like episodes) and from patients with NARP (neuropathy, ataxia and retinitis pigmentosa). These diseases also affect mitochondrial aerobic metabolism but are not known to predispose to tumor formation. To study in vivo the systemic consequences of defects in mitochondrial aerobic metabolism, we used a transgenic mouse model of late-onset mitochondrial myopathy. The mouse contains a transgene with an in-frame duplication of a segment of Twinkle, the mitochondrial replicative helicase, whose defects underlie the human disease progressive external ophthalmoplegia. This mouse model replicates the phenotype in the patients, particularly neuronal degeneration, mitochondrial myopathy, and subtle decrease of respiratory chain activity associated with mtDNA deletions. Due to the accumulation of mtDNA deletions, the mouse was named deletor. We first studied the consequences of FH- and of respiratory chain defects for energy metabolism in primary fibroblasts. To further characterize the effects of FH- and respiratory chain malfunction in primary fibroblasts at transcriptional level, we used expression microarrays. In order to understand the in vivo consequences of respiratory chain defects in vivo, we also studied the transcriptional consequences of Twinkle defects in deletor mice skeletal muscle, cerebellum and hippocampus. Fumarate accumulated in the FH- homozygous cells, but not in the compound heterozygous lines. However, virtually all FH- lines lacked cytoplasmic FH. Induction of glycolysis was common to FH-, MELAS and NARP fibroblasts. In deletor muscle glycolysis seemed to be upregulated. This was in contrast with deletor cerebellum and hippocampus, where mitochondrial biogenesis was in progress. Despite sharing a glycolytic pattern in energy metabolism, FH- and respiratory chain defects led to opposite consequences in redox environment. FH- was associated with reduced redox environment, while MELAS and NARP displayed evidences of oxidative stress. The deletor cerebellum had transcriptional induction of antioxidant defenses, suggesting increased production of reactive oxygen species. Since the fibroblasts do not represent the tissues where the tumors appear in FH- patients, we compared the fibroblast array data with the data from FH- leiomyomas and normal myometrium. This allowed the determination of the pathways and networks affected by FH-deficiency in primary cells that are also relevant for myoma formation. A key pathway regulating smooth muscle differentiation, SRF (serum response factor)-FOS-JUNB, was found to be downregulated in FH- cells and in myomas. While in the deletor mouse many pathways were affected in a tissue-specific basis, like FGF21 induction in the deletor muscle, others were systemic, such as the downregulation of ALAS2-linked heme synthesis in all deletor tissues analyzed. However, interestingly, even a tissue-specific response of FGF21 excretion could elicit a global starvation response. The work presented in this thesis has contributed to a better understanding of mitochondrial stress signalling and of pathways interpreting and transducing it to human pathology.

Immunodeficiencies, pathogens and sex in upper respiratory diseases

In the first part of this thesis the association of different forms of sinonasal diseases and plasma concentrations of C3, C4, immunoglobulins, immunoglobulin G subclasses, C4A and C4B gene numbers were studied in 287 adult patients and 150 sex-matched adult controls. Patients were well characterized and stratified into groups using strict clinical criteria and females and males were also studied as separate groups. Severe primary antibody antibody deficiencies were rare in patients coming to sinonasal operations. Female patients had more recurrent sinusitis and other mucosal infections and males had more nasal polyposis. Upregulation of complement activity was seen in acute rhinosinusitis patients (high levels of plasma C3, C4, and complement classical pathway activity CH50) and male patients coming to sinonasal operations (high levels of plasma C3 and C4). In females, total and partial C4B deficiencies and lower levels of IgG1 and IgG3 were associated with rhinosinusitis leading to sinonasal operations. C4A deficiencies were found to predispose to severe chronic rhinosinusitis in females and males. In female patients with chronic or recurrent rhinosinusitis with nasal polyposis C4B deficiencies seem to predispose to the disease, but in males with a similar disease C4B deficiencies seem to be protective. This suggests a different pathophysiology between sexes in this form of sinonasal disease. In the second part of this thesis work 213 children coming to elective tonsillectomy were studied and compared with 155 randomly selected school children. An association with recurrent upper respiratory tract infections and hypersensitivity disorders was seen especially in children under 7 years of age. However, this association was not seen in levels of specific IgE to respiratory allergens in the same age group. Both symptomatic respiratory allergy and specific IgE to respiratory allergens became more common in boys than girls over 7 years of age. We were able to show that although both rhinoviruses and bacterial pathogens were found in the tonsils, no association between their presence and clinical forms of tonsillar disease was seen. The ability of GAS to bind complement regulators FH and C4BP did not differ between strains causing tonsillar diseases or septicemia, suggesting that other virulence mechanisms of the bacteria are more important.

Is Mycoplasma bovis a missing component of the bovine respiratory disease complex in Australia?

Background: Bovine respiratory disease complex (BRDC) is a multi-factorial disease in which numerous factors, such as animal management, pathogen exposure and environmental conditions, contribute to the development of acute respiratory illness in feedlot cattle. The role of specific pathogens in the development of BRDC has been difficult to define because of the complex nature of the disease and the presence of implicated bacterial pathogens in the upper respiratory tract of healthy animals. Mycoplasma bovis is an important pathogen of cattle and recognised as a major contributor to cases of mastitis, caseonecrotic bronchopneumonia, arthritis and otitis media. To date, the role of M.bovis in the development of BRDC of Australian feeder cattle has not been investigated. Methods: In this review, the current literature pertaining to the role of M.bovis in BRDC is evaluated. In addition, preliminary data are presented that identify M.bovis as a potential contributor to BRDC in Australian feedlots, which has not been considered previously. Results and Conclusion: The preliminary results demonstrate detection of M.bovis in samples from all feedlots studied. When considered in the context of the reviewed literature, they support the inclusion of M.bovis on the list of pathogens to be considered during investigations into BRDC in Australia. © 2014 Australian Veterinary Association.

Survival analysis of time-to-event data in respiratory health research studies

This article provides a review of techniques for the analysis of survival data arising from respiratory health studies. Popular techniques such as the Kaplan–Meier survival plot and the Cox proportional hazards model are presented and illustrated using data from a lung cancer study. Advanced issues are also discussed, including parametric proportional hazards models, accelerated failure time models, time-varying explanatory variables, simultaneous analysis of multiple types of outcome events and the restricted mean survival time, a novel measure of the effect of treatment.