Investigation of the CACNA1A gene as a candidate for typical migraine susceptibility

Typical migraine is a complex neurological disorder comprised of two main subtypes: migraine with (MA) and without aura (MO). The disease etiology is still unclear, but family studies provide strong evidence that defective genes play an important role. Familial hemiplegic migraine (FHM) is a very rare and severe subtype of MA. It has been proposed that FHM and MA may have a similar genetic etiology. Therefore, genetic studies on FHM provide a useful model for investigating the more prevalent types of typical migraine. FHM in some families has been shown to be caused by mutations in a brain-specific P/Q-type calcium channel alpha1 subunit gene (CACNA1A) on chromosome 19p13. There has also been a report of a CACNA1A mutation being associated with MA in a patient from a family with predominant FHM. We have previously demonstrated suggestive linkage of typical migraine in a large Australian family to the FHM region on chromosome 19p13. These findings suggest that CACNA1A may also be implicated in the etiology of typical migraine in this pedigree. To investigate this possibility, we sequenced two patients carrying the critical susceptibility haplotype surrounding CACNA1A. No disease-causing mutations or polymorphisms were revealed in any of the 47 exons screened. To determine whether the CACNA1A gene was implicated in typical migraine susceptibility in the general Caucasian population, we also analyzed 82 independent pedigrees and a large case control group. We did not detect any linkage or association in these groups and conclude that if CACNA1A plays a role in typical migraine, it does not confer a major effect on the disease.

Familial typical migraine: Significant linkage and localization of a gene to Xq24-28

In a previous study we found evidence for an X-linked genetic component for familial typical migraine in two large Australian white pedigrees, designated MF7 and MF14. Significant excess allele sharing was indicated by nonparametric linkage (NPL) analysis using GENEHUNTER (P=0.031 and P=0.012, respectively), with a combined analysis of the two pedigrees showing further increased evidence for linkage, producing a maximum NPL score of 2.87 (P=0.011 ) at DXS 1123 on Xq27. The present study was aimed at refining the localization of the migraine X-chromosomal component by typing additional markers, performing haplotype analysis and applying a more powerful technique in the analysis of linkage data from these two pedigrees. Results from the haplotype analyses, coupled with linkage analyses that produced a peak GENEHUNTER-PLUS LOD* score of 2.388 (P=0.0005), provide compelling evidence for the presence of a migraine susceptibility locus on chromosome Xq24-28.

Evidence for an X-linked genetic component in familial typical migraine

Migraine is a common complex disorder that shows strong familial aggregation. There is a general increased prevalence of migraine in females compared with males, with recent studies indicating that migraine affects 18% of females compared with 6% of males. This preponderance of females among migraine sufferers coupled with evidence of an increased risk of migraine in first degree relatives of male probands but not in relatives of female probands suggests the possibility of an X-linked dominant gene. We report here the localization of a typical migraine susceptibility locus to the X chromosome. Of three large multigenerational migraine pedigrees two families showed significant excess allele sharing to Xq markers (P = 0.031 and P = 0.012). Overall analysis of data from all three pedigrees gave significant evidence in support of linkage and heterogeneity (HLOD = 3.1). These findings provide conclusive evidence that familial typical migraine is a heterogeneous disorder. We suggest that the localization of a migraine susceptibility locus to the X chromosome could in part explain the increased risk of migraine in relatives of male probands and may be involved in the increased female prevalence of this disorder.

Load frequency control in a microgrid : challenges and improvements

A microgrid can span over a large area, especially in rural townships. In such cases, the distributed generators (DGs) must be controlled in a decentralized fashion, based on the locally available measurements. The main concerns are control of system voltage magnitude and frequency, which can either lead to system instability or voltage collapse. In this chapter, the operational challenges of load frequency control in a microgrid are discussed and few methods are proposed to meet these challenges. In particular, issues of power sharing, power quality and system stability are addressed, when the system operates under decentralized control. The main focus of this chapter is to provide solutions to improve the system performance in different situations. The scenarios considered are (a) when the system stability margin is low, (b) when the line impedance has a high R to X ratio, (c) when the system contains unbalanced and/or distorted loads. Also a scheme is proposed in which a microgrid can be frequency isolated from a utility grid while being capable of bidirectional power transfer. In all these cases, the use of angle droop in converter interfaced DGs is adopted. It has been shown that this results in a more responsive control action compared to the traditional frequency based droop control.

Familial typical migraine: Linkage to chromosome 19p13 and evidence for genetic heterogeneity

Migraine is a frequent familial disorder that, in common with most multifactorial disorders, has an unknown etiology. The authors identified several families with multiple individuals affected by typical migraine using a single set of diagnostic criteria and studied these families for cosegregation between the disorder and markers on chromosome 19, the location of a mutation that causes a rare form of familial hemiplegic migraine (FHM). One large tested family showed both cosegregation and significant allele sharing for markers situated within or adjacent to the FHM locus. Multipoint GENEHUNTER results indicated significant excess allele sharing across a 12.6- cM region containing the FHM Ca2+ channel gene, CACNL1A4 (maximum nonparametric linkage Z score = 6.64, p = 0.0026), with a maximum parametric lod score of 1.92 obtained for a (CAG)(n) triplet repeat polymorphism situated in exon 47 of this gene. The CAG expansion did not, however, appear to be the cause of migraine in this pedigree. Other tested families showed neither cosegregation nor excess allele sharing to chromosome 19 markers. HOMOG analysis indicated heterogeneity, generating a maximum HLOD score of 3.6. It was concluded that Chr19 mutations either in the CACNL1A4 gene or a closely linked gene are implicated in some pedigrees with familial typical migraine, and that the disorder is genetically heterogeneous.

Evidence for allelic association of the dopamine β-hydroxylase gene (DBH) with susceptibility to typical migraine

Migraine is a debilitating neurological disorder characterized by recurrent attacks of severe headache. The disorder is highly prevalent, affecting approximately 12% of Caucasian populations. It is well known that migraine has a strong genetic component, although the type and number of genes involved is not yet clear. However, the calcium channel gene, CACNA1A, on chromosome 19 contains mutations responsible for familial hemiplegic migraine, a rare and severe subtype of migraine. There is also evidence to suggest that serotonin- and dopamine-related genes may be involved in the pathogenesis of migraine. This study employed a linkage and association approach to investigate neurotransmitter-related migraine candidate genes. Polymorphisms within the dopamine beta-hydroxylase (DBH) gene, serotonin transporter gene (SERT), and dopamine receptor gene (DRD2) were tested in 177 unrelated Caucasian migraineurs and 182 control individuals. In addition, an independent sample of 82 families affected with migraine was examined. Unrelated case-control association analysis of a DBH intragenic dinucleotide polymorphism indicated altered allelic distribution between migraine and control groups (L2=16.53, P=0.019). Furthermore, the transmission/disequilibrium test, which was implemented on the family data, also indicated distortion of allele transmission for the same DBH marker (L2=4.44, P=0.035). Together, these results provide evidence for allelic association of the DBH gene with typical migraine susceptibility (Fisher's combined P value=0.006) and indicate that further research into the role of the DBH gene in the etiology of migraine is warranted.

The ACEN Student Scholarship: a profile of financial hardship and Work Integrated Learning

An increasing emphasis on embedding Work-Integrated Learning (WIL) in the curriculum has impacted on teaching and learning approaches in Australian higher education institutions (Higher Education Base Funding Review: Final Report, 2011). Yet whilst the benefits and costs of these approaches have been identified (Bradley, Noonan, Nugent, & Scales, 2008; Patrick et al., 2009) insufficient attention has been paid to financial costs experienced by students studying subjects with a Work Integrated Learning component. In 2010 the Australian Collaborative Education Network (ACEN) responded to this issue by offering three modest student scholarships based on evidence of hardship. Data collected from over 1000 applicants between 2010 and 2012 indicate travel, accommodation, food, clothing, equipment and loss of income are of major concern especially for students on lengthy placements involving relocation. At the same time the Australian Federal Government’s review of base funding has recommended a detailed assessment of the costs of providing student placements across all disciplines - in particular health and education (DEEWR, 2011, p.94). This paper considers costs from the student perspective and highlights major concerns identified through ACEN scholarship applications over a three year period. The implications for ACEN are described and recommendations documented which outline ACEN’s role in ensuring that these issues are given greater consideration across the sector.

Evaluating MPPT converter topologies using a Matlab PV model

An accurate PV module electrical model is presented based on the Shockley diode equation. The simple model has a photo-current current source, a single diode junction and a series resistance, and includes temperature dependences. The method of parameter extraction and model evaluation in Matlab is demonstrated for a typical 60W solar panel. This model is used to investigate the variation of maximum power point with temperature and isolation levels. A comparison of buck versus boost maximum power point tracker (MPPT) topologies is made, and compared with a direct connection to a constant voltage (battery) load. The boost converter is shown to have a slight advantage over the buck, since it can always track the maximum power point.

Evaluating MPPT converter topologies using a MATLAB PV model

An accurate PV module electrical model is presented based on the Shockley diode equation. The simple model has a photo-current current source, a single diode junction and a series resistance, and includes temperature dependences. The method of parameter extraction and model evaluation in Matlab is demonstrated for a typical 60W solar panel. This model is used to investigate the variation of maximumpower point with temperature and insolation levels. A comparison of buck versus boostmaximum power point tracker (MPPT) topologies is made, and compared with a direct connection to a constant voltage (battery) load. The boost converter is shown to have a slight advantage over the buck, since it can always track the maximum power point.

Ultimate flexural limit states analysis of prestressed concrete sleeper

Railway is one of the most important, reliable and widely used means of transportation, carrying freight, passengers, minerals, grains, etc. Thus, research on railway tracks is extremely important for the development of railway engineering and technologies. The safe operation of a railway track is based on the railway track structure that includes rails, fasteners, pads, sleepers, ballast, subballast and formation. Sleepers are very important components of the entire structure and may be made of timber, concrete, steel or synthetic materials. Concrete sleepers were first installed around the middle of last century and currently are installed in great numbers around the world. Consequently, the design of concrete sleepers has a direct impact on the safe operation of railways. The "permissible stress" method is currently most commonly used to design sleepers. However, the permissible stress principle does not consider the ultimate strength of materials, probabilities of actual loads, and the risks associated with failure, all of which could lead to the conclusion of cost-ineffectiveness and over design of current prestressed concrete sleepers. Recently the limit states design method, which appeared in the last century and has been already applied in the design of buildings, bridges, etc, is proposed as a better method for the design of prestressed concrete sleepers. The limit states design has significant advantages compared to the permissible stress design, such as the utilisation of the full strength of the member, and a rational analysis of the probabilities related to sleeper strength and applied loads. This research aims to apply the ultimate limit states design to the prestressed concrete sleeper, namely to obtain the load factors of both static and dynamic loads for the ultimate limit states design equations. However, the sleepers in rail tracks require different safety levels for different types of tracks, which mean the different types of tracks have different load factors of limit states design equations. Therefore, the core tasks of this research are to find the load factors of the static component and dynamic component of loads on track and the strength reduction factor of the sleeper bending strength for the ultimate limit states design equations for four main types of tracks, i.e., heavy haul, freight, medium speed passenger and high speed passenger tracks. To find those factors, the multiple samples of static loads, dynamic loads and their distributions are needed. In the four types of tracks, the heavy haul track has the measured data from Braeside Line (A heavy haul line in Central Queensland), and the distributions of both static and dynamic loads can be found from these data. The other three types of tracks have no measured data from sites and the experimental data are hardly available. In order to generate the data samples and obtain their distributions, the computer based simulations were employed and assumed the wheel-track impacts as induced by different sizes of wheel flats. A valid simulation package named DTrack was firstly employed to generate the dynamic loads for the freight and medium speed passenger tracks. However, DTrack is only valid for the tracks which carry low or medium speed vehicles. Therefore, a 3-D finite element (FE) model was then established for the wheel-track impact analysis of the high speed track. This FE model has been validated by comparing its simulation results with the DTrack simulation results, and with the results from traditional theoretical calculations based on the case of heavy haul track. Furthermore, the dynamic load data of the high speed track were obtained from the FE model and the distributions of both static and dynamic loads were extracted accordingly. All derived distributions of loads were fitted by appropriate functions. Through extrapolating those distributions, the important parameters of distributions for the static load induced sleeper bending moment and the extreme wheel-rail impact force induced sleeper dynamic bending moments and finally, the load factors, were obtained. Eventually, the load factors were obtained by the limit states design calibration based on reliability analyses with the derived distributions. After that, a sensitivity analysis was performed and the reliability of the achieved limit states design equations was confirmed. It has been found that the limit states design can be effectively applied to railway concrete sleepers. This research significantly contributes to railway engineering and the track safety area. It helps to decrease the failure and risks of track structure and accidents; better determines the load range for existing sleepers in track; better rates the strength of concrete sleepers to support bigger impact and loads on railway track; increases the reliability of the concrete sleepers and hugely saves investments on railway industries. Based on this research, many other bodies of research can be promoted in the future. Firstly, it has been found that the 3-D FE model is suitable for the study of track loadings and track structure vibrations. Secondly, the equations for serviceability and damageability limit states can be developed based on the concepts of limit states design equations of concrete sleepers obtained in this research, which are for the ultimate limit states.

Environments For Healthy Living (EFHL) Griffith birth cohort study : characteristics of sample and profile of antenatal exposures

Background The Environments for Healthy Living (EFHL) study is a repeated sample, longitudinal birth cohort in South East Queensland, Australia. We describe the sample characteristics and profile of maternal, household, and antenatal exposures. Variation and data stability over recruitment years were examined. Methods Four months each year from 2006, pregnant women were recruited to EFHL at routine antenatal visits on or after 24 weeks gestation, from three public maternity hospitals. Participating mothers completed a baseline questionnaire on individual, familial, social and community exposure factors. Perinatal data were extracted from hospital birth records. Descriptive statistics and measures of association were calculated comparing the EFHL birth sample with regional and national reference populations. Data stability of antenatal exposure factors was assessed across five recruitment years (2006–2010 inclusive) using the Gamma statistic for ordinal data and chi-squared for nominal data. Results Across five recruitment years 2,879 pregnant women were recruited which resulted in 2904 live births with 29 sets of twins. EFHL has a lower representation of early gestational babies, fewer still births and a lower percentage of low birth weight babies, when compared to regional data. The majority of women (65%) took a multivitamin supplement during pregnancy, 47% consumed alcohol, and 26% reported having smoked cigarettes. There were no differences in rates of a range of antenatal exposures across five years of recruitment, with the exception of increasing maternal pre-pregnancy weight (p=0.0349), decreasing rates of high maternal distress (p=0.0191) and decreasing alcohol consumption (p<0.0001). Conclusions The study sample is broadly representative of births in the region and almost all factors showed data stability over time. This study, with repeated sampling of birth cohorts over multiple years, has the potential to make important contributions to population health through evaluating longitudinal follow-up and within cohort temporal effects.

The safety profile of perflutren microsphere contrast echocardiography during rest and stress imaging : results from an Australian multicentre cohort

Background Contrast enhanced echocardiography (CEE) is utilised when sub-optimal image quality results in non-diagnostic echocardiograms. However, there have been numerous safety notices issued by regulatory authorities regarding rare but potentially serious adverse reactions (AR). This multi-centre, retrospective analysis was performed to assess the short-term safety of CEE in a broad range of indications. Methods All CEE performed over 58 months at three institutions were assessed for AR within 30 min. Results A total of 5956 CEE were performed in 5576 patients. A total of 4903 were stress CEE and 1053 resting CCE.Bolus administration in 5719, infusion in 237 cases; 89.9% of CCE were outpatients. Commonest CEE indication was functional stress testing (82.3%). There were 16 AR related to CEE (0.27%). All AR were mild, transient and all patients made a full recovery. No cases of serious anaphylaxis or death within 30 min of contrast administration. Comparing those with and without an AR, there were no significant differences in age, gender, BMI, LVEF, patient location, exam type or RVSP. There was a slightly increased likelihood of an AR during infusion versus bolus dosing (p = 0.02). Conclusion CEE is a safe investigation in a broad range of indications and clinical scenarios. AR are very rare, mild and transient.

Dynamic load-sharing of longitudinal-connected air suspensions of a tri-axle semi-trailer

The effects of suspension parameters and driving conditions on dynamic load-sharing of longitudinal-connected air suspensions of a tri-axle semi-trailer are investigated in this study. A novel nonlinear model of a multi-axle semi-trailer with longitudinal-connected air suspensions is formulated based on fluid mechanics and thermodynamics and validated through test results. The effects of road surface conditions, driving speeds, air line inside diameter and connector inside diameter on dynamic load-sharing capability of the semi-trailer were analyzed in terms of load-sharing criteria. Simulation results indicate that, when larger air lines and connectors are employed, the DLSC (Dynamic Load-Sharing Coefficient) optimization ratio reaches its peak value when the road roughness is medium. The optimization ratio fluctuates in a complex manner as driving speed increases. The results also indicate that if the air line inside diameter is always assumed to be larger than the connector inside diameter, the influence of air line inside diameter on load-sharing is more significant than that of the connector inside diameter. The proposed approach can be used for further study of the influence of additional factors (such as vehicle load, static absolute air pressure and static height of air spring) on load-sharing and the control methods for multi-axle air suspensions with longitudinal air line.