Unique X-linked familial FSGS with co-segregating heart block disorder is associated with a mutation in the NXF5 gene

Focal segmental glomerulosclerosis (FSGS) is the consequence of a disease process that attacks the kidney's filtering system, causing serious scarring. More than half of FSGS patients develop chronic kidney failure within 10 years, ultimately requiring dialysis or renal transplantation. There are currently several genes known to cause the hereditary forms of FSGS (ACTN4, TRPC6, CD2AP, INF2, MYO1E and NPHS2). This study involves a large, unique, multigenerational Australian pedigree in which FSGS co-segregates with progressive heart block with apparent X-linked recessive inheritance. Through a classical combined approach of linkage and haplotype analysis, we identified a 21.19 cM interval implicated on the X chromosome. We then used a whole exome sequencing approach to identify two mutated genes, NXF5 and ALG13, which are located within this linkage interval. The two mutations NXF5-R113W and ALG13-T141L segregated perfectly with the disease phenotype in the pedigree and were not found in a large healthy control cohort. Analysis using bioinformatics tools predicted the R113W mutation in the NXF5 gene to be deleterious and cellular studies support a role in the stability and localization of the protein suggesting a causative role of this mutation in these co-morbid disorders. Further studies are now required to determine the functional consequence of these novel mutations to development of FSGS and heart block in this pedigree and to determine whether these mutations have implications for more common forms of these diseases in the general population.

Functional analysis of missense variants in the TRESK (KCNK18) K+ channel

A loss of function mutation in the TRESK K2P potassium channel (KCNK18), has recently been linked with typical familial migraine with aura. We now report the functional characterisation of additional TRESK channel missense variants identified in unrelated patients. Several variants either had no apparent functional effect, or they caused a reduction in channel activity. However, the C110R variant was found to cause a complete loss of TRESK function, yet is present in both sporadic migraine and control cohorts, and no variation in KCNK18 copy number was found. Thus despite the previously identified association between loss of TRESK channel activity and migraine in a large multigenerational pedigree, this finding indicates that a single non-functional TRESK variant is not alone sufficient to cause typical migraine and highlights the genetic complexity of this disorder. Migraine is a common, disabling neurological disorder with a genetic, environmental and in some cases hormonal component. It is characterized by attacks of severe, usually unilateral and throbbing headache, can be accompanied by nausea, vomiting and photophobia and is clinically divided into two main subtypes, migraine with aura (MA) when a migraine is accompanied by transient and reversible focal neurological symptoms and migraine without aura (MO)1. The multifactorial and clinical heterogeneity of the disorder have considerably hindered the identification of common migraine susceptibility genes and most of our current understanding comes from the studies of familial hemiplegic migraine (FHM), a rare monogenic autosomal dominant form of MA2. So far, the three susceptibility genes that have been convincingly identified in FHM families all encode ion channels or transporters: CACNA1A encoding the α1 subunit of the Cav2.1 calcium channel3, SCN1A encoding the Nav1.1 sodium channel4 and ATP1A2 encoding the α2 subunit of the Na+/K+ pump5. It is believed that mutations in these genes may lead to increased efflux of glutamate and potassium in the synapse and thereby cause migraine by rendering the brain more susceptible to cortical spreading depression (CSD)6 which is thought to play a role in initiating a migraine attack7,8. However, these genes have not to date been implicated in common forms of migraine9. Nevertheless, current opinion suggests that typical migraine, like FHM, is also disorder of neuronal excitability, ion homeostasis and neurotransmitter release10,11,12. Mutations in the SLC4A4 gene encoding the sodium-bicarbonate cotransporter NBCe1, have recently been implicated in several different forms of migraine13, and a variety of genes involved in glutamate homeostasis (PGCP, MTDH14 and LRP115) and a cation channel (TRPM8)15 have also recently been implicated in migraine via genome-wide association studies. Ion channels are therefore highly likely to play an important role in the pathogenesis of typical migraine. TRESK (KCNK18), is a member of the two-pore domain (K2P) family of potassium channels involved in the control of cellular electrical excitability16. Regulation of TRESK activity by the calcium-dependent phosphatase calcineurin17, as well as its expression in dorsal root ganglia (DRG)18 and trigeminal ganglia (TG)19,20 has led to a proposed role for this channel in a variety of pain pathways. In a recent study, a frameshift mutation (F139Wfsx24) in TRESK was identified in a large multigenerational pedigree where it co-segregated perfectly with typical MA and a significant genome-wide linkage LOD score of 3.0. Furthermore, functional analysis revealed that this mutation caused a complete loss of TRESK function and that the truncated subunit was also capable of down regulating wild-type channel function. This therefore highlighted KCNK18 as potentially important candidate gene and suggested that TRESK dysfunction might play a possible role in the pathogenesis of familial migraine with visual aura20. Additional screening for KCNK18 mutations in unrelated sporadic migraine and control cohorts also identified a number of other missense variants; R10G, A34V, C110R, S231P and A233V20. The A233V variant was found only in the control cohort, whilst A34V was identified in a single Australian migraine proband for which family samples were not available, but it was not detected in controls. By contrast, the R10G, C110R, and S231P variants were found in both migraineurs and controls in both cohorts. In this study, we have investigated the functional effect of these variants to further probe the potential association of TRESK dysfunction with typical migraine.

Blast induced ground shock effects on pile foundations

Due to increased number of terrorist attacks in recent years, loads induced by explosions need to be incorporated in building designs. For safer performance of a structure, its foundation should have sufficient strength and stability. Therefore, prior to any reconstruction or rehabilitation of a building subjected to blast, it is important to examine adverse effects on the foundation caused by blast induced ground shocks. This paper evaluates the effects of a buried explosion on a pile foundation. It treats the dynamic response of the pile in saturated sand, using explicit dynamic nonlinear finite element software LS-DYNA. The blast induced wave propagation in the soil and the horizontal deformation of pile are presented and the results are discussed. Further, a parametric study is carried out to evaluate the effect of varying the explosive shape on the pile response. This information can be used to evaluate the vulnerability of piled foundations to credible blast events as well as develop guidance for their design.

Shorter telomere length in peripheral blood cells associated with migraine in women

Objective To evaluate relative telomere length of female migraine patients. Background Migraine is a debilitating disorder affecting 6-28% of the population. Studies on the mechanisms of migraine have demonstrated genetic causes but the pathophysiology and subcellular effects of the disease remain poorly understood. Shortened telomere length is associated with age-related or chronic diseases, and induced stresses. Migraine attacks may impart significant stress on cellular function, thus this study investigates a correlation between shortening of telomeres and migraine. Methods Relative telomere length was measured using a previously described quantitative polymerase chain reaction method. A regression analysis was performed to assess differences in mean relative telomere length between migraine patients and healthy controls. Results The leukocyte telomeres of a cohort of 142 Caucasian female migraine subjects aged 18-77 years and 143 matched 17-77-year-old healthy control Caucasian women were examined.A significantly shorter relative telomere length was observed in the migraine group compared with the control group after adjusting for age and body mass index (P = .001). In addition, age of onset was observed to associate with the loss of relative telomere length, especially at early age of onset (<17 years old). No association was observed between relative telomere length and the severity and frequency of migraine attacks and the duration of migraine. Conclusion Telomeres are shorter in migraine patients and there is more variation in telomere length in migraine patients.

Investigation of Gamma-aminobutyric acid (GABA) A receptors genes and migraine susceptibility

Background Migraine is a neurological disorder characterized by recurrent attacks of severe headache, affecting around 12% of Caucasian populations. It is well known that migraine has a strong genetic component, although the number and type of genes involved is still unclear. Prior linkage studies have reported mapping of a migraine gene to chromosome Xq 24–28, a region containing a cluster of genes for GABA A receptors (GABRE, GABRA3, GABRQ), which are potential candidate genes for migraine. The GABA neurotransmitter has been implicated in migraine pathophysiology previously; however its exact role has not yet been established, although GABA receptors agonists have been the target of therapeutic developments. The aim of the present research is to investigate the role of the potential candidate genes reported on chromosome Xq 24–28 region in migraine susceptibility. In this study, we have focused on the subunit GABA A receptors type ε (GABRE) and type θ (GABRQ) genes and their involvement in migraine. Methods We have performed an association analysis in a large population of case-controls (275 unrelated Caucasian migraineurs versus 275 controls) examining a set of 3 single nucleotide polymorphisms (SNPs) in the coding region (exons 3, 5 and 9) of the GABRE gene and also the I478F coding variant of the GABRQ gene. Results Our study did not show any association between the examined SNPs in our test population (P > 0.05). Conclusion Although these particular GABA receptor genes did not show positive association, further studies are necessary to consider the role of other GABA receptor genes in migraine susceptibility.

Minor head trauma – induced sporadic hemiplegic migraine coma

Familial hemiplegic migraine is a severe, rare subtype of migraine. Gene mutations on chromosome 19 have been identified in the calcium channel, voltage-dependent, P/Q type, alpha-1A subunit gene (chromosome 19p13) for familial hemiplegic migraine. Recently a gene mutation (Serine-218-Leucine) for a dramatic syndrome associated with familial hemiplegic migraine, commonly named “migraine coma”, has implicated exon 5 of this gene. The occurrence of trivial head trauma, in such familial hemiplegic migraine patients, may also be complicated by severe, sometimes even fatal, cerebral edema and coma occurring after a lucid interval. Sporadic hemiplegic migraine shares a similar spectrum of clinical presentation and genetic heterogeneity. The case report presented in this article implicates the involvement of the Serine-218-Leucine mutation in the extremely rare disorder of minor head trauma–induced migraine coma. We conclude that the Serine-218-Leucine mutation in the calcium channel, voltage-dependent, P/Q type, alpha-1A subunit gene is involved in sporadic hemiplegic migraine, delayed cerebral edema and coma after minor head trauma.

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.

Analysis of nonlinear sequences and streamciphers

Streamciphers are common cryptographic algorithms used to protect the confidentiality of frame-based communications like mobile phone conversations and Internet traffic. Streamciphers are ideal cryptographic algorithms to encrypt these types of traffic as they have the potential to encrypt them quickly and securely, and have low error propagation. The main objective of this thesis is to determine whether structural features of keystream generators affect the security provided by stream ciphers.These structural features pertain to the state-update and output functions used in keystream generators. Using linear sequences as keystream to encrypt messages is known to be insecure. Modern keystream generators use nonlinear sequences as keystream.The nonlinearity can be introduced through a keystream generator's state-update function, output function, or both. The first contribution of this thesis relates to nonlinear sequences produced by the well-known Trivium stream cipher. Trivium is one of the stream ciphers selected in a final portfolio resulting from a multi-year project in Europe called the ecrypt project. Trivium's structural simplicity makes it a popular cipher to cryptanalyse, but to date, there are no attacks in the public literature which are faster than exhaustive keysearch. Algebraic analyses are performed on the Trivium stream cipher, which uses a nonlinear state-update and linear output function to produce keystream. Two algebraic investigations are performed: an examination of the sliding property in the initialisation process and algebraic analyses of Trivium-like streamciphers using a combination of the algebraic techniques previously applied separately by Berbain et al. and Raddum. For certain iterations of Trivium's state-update function, we examine the sets of slid pairs, looking particularly to form chains of slid pairs. No chains exist for a small number of iterations.This has implications for the period of keystreams produced by Trivium. Secondly, using our combination of the methods of Berbain et al. and Raddum, we analysed Trivium-like ciphers and improved on previous on previous analysis with regards to forming systems of equations on these ciphers. Using these new systems of equations, we were able to successfully recover the initial state of Bivium-A.The attack complexity for Bivium-B and Trivium were, however, worse than exhaustive keysearch. We also show that the selection of stages which are used as input to the output function and the size of registers which are used in the construction of the system of equations affect the success of the attack. The second contribution of this thesis is the examination of state convergence. State convergence is an undesirable characteristic in keystream generators for stream ciphers, as it implies that the effective session key size of the stream cipher is smaller than the designers intended. We identify methods which can be used to detect state convergence. As a case study, theMixer streamcipher, which uses nonlinear state-update and output functions to produce keystream, is analysed. Mixer is found to suffer from state convergence as the state-update function used in its initialisation process is not one-to-one. A discussion of several other streamciphers which are known to suffer from state convergence is given. From our analysis of these stream ciphers, three mechanisms which can cause state convergence are identified.The effect state convergence can have on stream cipher cryptanalysis is examined. We show that state convergence can have a positive effect if the goal of the attacker is to recover the initial state of the keystream generator. The third contribution of this thesis is the examination of the distributions of bit patterns in the sequences produced by nonlinear filter generators (NLFGs) and linearly filtered nonlinear feedback shift registers. We show that the selection of stages used as input to a keystream generator's output function can affect the distribution of bit patterns in sequences produced by these keystreamgenerators, and that the effect differs for nonlinear filter generators and linearly filtered nonlinear feedback shift registers. In the case of NLFGs, the keystream sequences produced when the output functions take inputs from consecutive register stages are less uniform than sequences produced by NLFGs whose output functions take inputs from unevenly spaced register stages. The opposite is true for keystream sequences produced by linearly filtered nonlinear feedback shift registers.

Bridging the biology of the ovine TRALI model – human inflammatory cell responses to TRALI inducing supernatants

Background Transfusion-related acute lung injury (TRALI) is a serious and potentially fatal consequence of transfusion. A two-event TRALI model demonstrated date-of-expiry - day (D) 5 platelet (PLT) and D42 packed red blood cell (PRBC) supernatants (SN) induced TRALI in LPS-treated sheep. We have adapted a whole blood transfusion culture model as an investigative bridge between the ovine TRALI model human responses to transfusion. Methods A whole blood transfusion model was adapted to replicate the ovine model - specifically +/- 0.23μg/mL LPS as the first event and 10% SN volume (transfusion) as the second event. Four pooled SN from blood products, previously used in the TRALI ovine model, were investigated: D1-PLT, D5-PLT, D1-PRBC, and D42-PRBC. Fresh human whole blood (recipient) was mixed with combinations of LPS and BP-SN stimuli and incubated in vitro for 6 hrs. Addition of golgi plug enabled measurement of monocyte cytokine production (IL-6, IL-8, IL-10, IL-12, TNF-α, IL-1α, CXCL-5, IP-10, MIP-1α, MCP-1) using multi-colour flow cytometry. Responses for 6 recipients were assessed. Results In the presence of LPS, D42-PRBC-SN significantly increased monocyte IL-6 (P=0.031), IL-8 (P=0.016) and IL-1α (P=0.008) production compared to D1-PRBC-SN. This response to D42-PRBC-SN was LPS-dependent, and was not evident in non-LPSstimulated controls. This response was also specific to D42-PRBC-SN, as similar changes were not evident for the D5-PLT-SN, compared to the D1-PLT-SN, regardless of the presence of LPS. D5-PLT-SN significantly increased IL-12 production (P=0.024) compared to D1-PLT-SN. This response was again LPS-dependent. Conclusions These data demonstrate a novel two-event mechanism of monocyte inflammatory response that was dependent upon both the presence of date-of-expiry blood product SN and LPS. Further, these results demonstrate different cytokines responses induced by date-of-expiry PLT-SN and PRBC-SN. These data are consistent with the evidence from the ovine TRALI model, and enhancing its relevance to transfusion related changes in humans.

Sleepiness : how a biological drive can influence other risky road user behaviours

The Safe System approach to road safety utilises a holistic view of the interactions among vehicles, roads and road users. Yet, the contribution of each of these factors to crashes is vastly different. The role of road users is widely acknowledged as an overwhelming contributor to road crashes. Substantial gains have been made with improvements to vehicle and roads over a number of years. However, improvements of the road user’s behaviour has been (in some cases) less substantial. A road user behaviour that is relatively unregulated is driver sleepiness, which is part of the ‘fatal five’ of risky road user behaviours. The effect of sleepiness is ubiquitous – sleepiness is a state that most, if not all drivers on our roads has experienced, and is habitually exposed to. The quality and quantity of daily sleep is integral to our level of neurobehavioural performance during wakefulness and as such can have a compounding effect on a number of other risky driving behaviours. This paper will discuss the potential influence of sleepiness as an interceding factor for a number of risky driving behaviours. Little effort has been given to increasing awareness of the deleterious and wide ranging effects that sleepiness has on road safety. Given the wide ranging influence of sleepiness, improvements of ‘sleep health’ as a protective factor at the community or individual level could lead to significant reductions in road trauma and increases of general well being. A discussion of potential actions to reduce sleepiness is required if reductions of road trauma are to continue.

The association between cold spells and pediatric outpatient visits for asthma in Shanghai, China

Background Asthma is a serious global health problem. However, few studies have investigated the relationship between cold spells and pediatric outpatient visits for asthma. Objective To examine the association between cold spells and pediatric outpatient visits for asthma in Shanghai, China. Methods We collected daily data on pediatric outpatient visits for asthma, mean temperature, relative humidity, and ozone from Shanghai between 1 January 2007 and 31 December 2009. We defined cold spells as four or more consecutive days with temperature below the 5th percentile of temperature during 2007–2009. We used a Poisson regression model to examine the impact of temperature on pediatric outpatient visits for asthma in cold seasons during 2007 and 2009. We examined the effect of cold spells on asthma compared with non-cold spell days. Results There was a significant relationship between cold temperatures and pediatric outpatient visits for asthma. The cold effects on children's asthma were observed at different lags. The lower the temperatures, the higher the risk for asthma attacks among children. Conclusion Cold temperatures, particularly cold spells, significantly increase the risk of pediatric outpatient visits for asthma. The findings suggest that asthma children need to be better protected from cold effects in winter.

Characteristics of police-reported road traffic crashes in Ethiopia over a six year period

Ethiopia has one of Africa’s fastest growing non-oil producing economies and an increasing level of motorisation (AfDB, OECD, UNDP, & UNECA, 2012). This rapidly increasing mobility has created some unique road safety concerns; however there is scant published information and related commentary (United Nations Economic Commission for Africa, 2009). The objective of this paper is to quantify police-reported traffic crashes in Ethiopia and characterise the existing state of road safety. Six years (July 2005 - June 2011) of police-reported crash data were analysed, consisting of 12,140 fatal and 29,454 injury crashes on the country’s road network. The 12,140 fatal crashes involved 1,070 drivers, 5,702 passengers, and 7,770 pedestrians, totalling 14,542 fatalities, an average of 1.2 road user fatalities per crash. An important and glaring trend that emerges is that more than half of the fatalities in Ethiopia involve pedestrians. The majority of the crashes occur during daytime hours, involve males, and involve persons in the 18-50 age group—Ethiopia’s active workforce. Crashes frequently occur in mid blocks or roadways. The predominant collision between motor vehicles and pedestrians was a rollover on a road tangent section. Failing to observe the priority of pedestrians and speeding were the major causes of crashes attributed by police. Trucks and minibus taxis were involved in the majority of crashes, while automobiles (small vehicles) were less involved in crashes relative to other vehicle types, partially because small vehicles tend to be driven fewer kilometres per annum. These data illustrate and justify a high priority to identify and implement effective programs, policies, and countermeasures focused on reducing pedestrian crashes.

Injury severity of pedestrian crashes in Singapore

Singapore is a highly urbanized city-state country where walking is an important mode of travel. Pedestrians form about 25% of road fatalities every year, making them one of the most vulnerable road user groups in Singapore. Engineering measures like provision of overhead pedestrian crossings and raised zebra crossings tend to address pedestrian safety in general, but there may be occasions where pedestrians are particularly vulnerable so that targeted interventions are more appropriate. The objective of this study is to identify factors and situations that affect the injury severity of pedestrians involved in traffic crashes. Six years of crash data from 2003 to 2008 containing around four thousands pedestrian crashes at roadway segments were analyzed. Injury severity of pedestrians—recorded as slight injury, major injury and fatal—were modeled as a function of roadway characteristics, traffic features, environmental factors and pedestrian demographics by an ordered probit model. Results suggest that the injury severity of pedestrians involved in crashes during night time is higher indicating that pedestrian visibility during night is a key issue in pedestrian safety. The likelihood of fatal or serious injuries is higher for crashes on roads with high speed limit, center and median lane of multi-lane roads, school zones, roads with two-way divided traffic type, and when pedestrians cross the roads. Elderly pedestrians appear to be involved in fatal and serious injury crashes more when they attempt to cross the road without using nearby crossing facilities. Specific countermeasures are recommended based on the findings of this study.

Efficacy of proxy definitions for identification of fatigue/sleep-related crashes : an Australian evaluation

Fatigue/sleepiness is recognised as an important contributory factor in fatal and serious injury road traffic incidents (RTIs), however, identifying fatigue/sleepiness as a causal factor remains an uncertain science. Within Australia attending police officers at a RTI report the causal factors; one option is fatigue/sleepiness. In some Australian jurisdictions police incident databases are subject to post hoc analysis using a proxy definition for fatigue/sleepiness. This secondary analysis identifies further RTIs caused by fatigue/sleepiness not initially identified by attending officers. The current study investigates the efficacy of such proxy definitions for attributing fatigue/sleepiness as a RTI causal factor. Over 1600 Australian drivers were surveyed regarding their experience and involvement in fatigue/sleep-related RTIs and near-misses during the past five years. Driving while fatigued/sleepy had been experienced by the majority of participants (66.0% of participants). Fatigue/sleep-related near misses were reported by 19.1% of participants, with 2.4% being involved in a fatigue/sleep-related RTI. Examination of the characteristics for the most recent event (either a near miss or crash) found that the largest proportion of incidents (28.0%) occurred when commuting to or from work, followed by social activities (25.1%), holiday travel (19.8%), or for work purposes (10.1%). The fatigue/sleep related RTI and near-miss experience of a representative sample of Australian drivers does not reflect the proxy definitions used for fatigue/sleepiness identification. In particular those RTIs that occur in urban areas and at slow speeds may not be identified. While important to have a strategy for identifying fatigue/sleepiness related RTIs proxy measures appear best suited to identifying specific subsets of such RTIs.

Formalising human recognition : a fundamental building block for security proofs

A fundamental part of many authentication protocols which authenticate a party to a human involves the human recognizing or otherwise processing a message received from the party. Examples include typical implementations of Verified by Visa in which a message, previously stored by the human at a bank, is sent by the bank to the human to authenticate the bank to the human; or the expectation that humans will recognize or verify an extended validation certificate in a HTTPS context. This paper presents general definitions and building blocks for the modelling and analysis of human recognition in authentication protocols, allowing the creation of proofs for protocols which include humans. We cover both generalized trawling and human-specific targeted attacks. As examples of the range of uses of our construction, we use the model presented in this paper to prove the security of a mutual authentication login protocol and a human-assisted device pairing protocol.