Cerebral cortex activation mapping upon electrical muscle stimulation by 32-channel time-domain functional near-infrared spectroscopy

The application of different EMS current thresholds on muscle activates not only the muscle but also peripheral sensory axons that send proprioceptive and pain signals to the cerebral cortex. A 32-channel time-domain fNIRS instrument was employed to map regional cortical activities under varied EMS current intensities applied on the right wrist extensor muscle. Eight healthy volunteers underwent four EMS at different current thresholds based on their individual maximal tolerated intensity (MTI), i.e., 10 % < 50 % < 100 % < over 100 % MTI. Time courses of the absolute oxygenated and deoxygenated hemoglobin concentrations primarily over the bilateral sensorimotor cortical (SMC) regions were extrapolated, and cortical activation maps were determined by general linear model using the NIRS-SPM software. The stimulation-induced wrist extension paradigm significantly increased activation of the contralateral SMC region according to the EMS intensities, while the ipsilateral SMC region showed no significant changes. This could be due in part to a nociceptive response to the higher EMS current intensities and result also from increased sensorimotor integration in these cortical regions.

Attribute-based functional encryption on lattices

We introduce a broad lattice manipulation technique for expressive cryptography, and use it to realize functional encryption for access structures from post-quantum hardness assumptions. Specifically, we build an efficient key-policy attribute-based encryption scheme, and prove its security in the selective sense from learning-with-errors intractability in the standard model.

Calligraphy and causation : two obstetric management cases - Hirst v Sydney South West Area Health and King v Western Sydney local health network

Two recent decisions of the Supreme Court of New South Wales in the context of obstetric management have highlighted firstly, the importance of keeping legible, accurate and detailed medical records; and secondly, the challenges faced by those seeking to establish causation, particularly where epidemiological evidence is relied upon...

In vitro functional characterisation of IGF-I : VN-induced breast cancer progression

Members of the insulin-like growth factor (IGF) family have been shown to play critical roles in normal growth and development, as well as in tumour biology. The IGF system is complex and the biological effects of the IGFs are determined by their diverse interactions between many molecules, including their interactions with extracellular matrix (ECM) proteins. Recent studies have demonstrated that IGFs associate with the ECM protein vitronectin (VN) through IGF-binding proteins (IGFBP) and that this interaction modulates IGF-stimulated biological functions, namely cell migration and cell survival through the cooperative involvement of the type-I IGF receptor (IGF-1R) and VN-binding integrins. Since IGFs play important roles in the transformation and progression of breast cancer and VN has been found to be over-expressed at the leading edge of breast tumours, this project aimed to describe the effects of IGF-I:VN interactions on breast cell function. This was undertaken to dissect the molecular mechanisms underlying IGF-I:VN-induced responses and to design inhibitors to block the effects of such interactions. The studies described herein demonstrate that the increase in migration of MCF-7 breast cancer cells in response to the IGF-I:IGFBP-5:VN complex is accompanied by differential expression of genes known to be involved in migration, invasion and/or survival, including Tissue-factor (TF), Stratifin (SFN), Ephrin-B2, Sharp-2 and PAI-1. This „migration gene signature‟ was confirmed using real-time PCR analysis. Substitution of the native IGF-I within the IGF-I:IGFBP:VN complex with the IGF-I analogue, \[L24]\[A31]-IGF-I, which has a reduced affinity for the IGF-1R, failed to stimulate cell migration and interestingly, also failed to induce the differential gene expression. This supports the involvement of the IGF-1R in mediating these changes in gene expression. Furthermore, lentiviral shRNA-mediated stable knockdown of TF and SFN completely abrogated the increased cell migration induced by IGF-I:IGFBP:VN complexes in MCF-7 cells. Indeed, when these cells were grown in 3D Matrigel™ cultures a decrease in the overall size of the 3D spheroids in response to the IGF-I:IGFBP:VN complexes was observed compared to the parental MCF-7 cells. This suggests that TF and SFN have a role in complex-stimulated cell survival. Moreover, signalling studies performed on cells with the reduced expression of either TF or SFN had a decreased IGF-1R activation, suggesting the involvement of signalling pathways downstream of IGF-1R in TF- and/or SFN-mediated cell migration and cell survival. Taken together, these studies provide evidence for a common mechanism activated downstream of the IGF-1R that induces the expression of the „migration gene signature‟ in response to the IGF-I:IGFBP:VN complex that confers breast cancer cells the propensity to migrate and survive. Given the functional significance of the interdependence of ECM and growth factor (GF) interactions in stimulating processes key to breast cancer progression, this project aimed at developing strategies to prevent such growth factor:ECM interactions in an effort to inhibit the downstream functional effects. This may result in the reduction in the levels of ECM-bound IGF-I present in close proximity to the cells, thereby leading to a reduction in the stimulation of IGF-1R present on the cell surface. Indeed, the inhibition of IGF-I-mediated effects through the disruption of its association with ECM would not alter the physiological levels of IGF-I and potentially only exert effects in situations where abnormal over expression of ECM proteins are found; namely carcinomas and hyperproliferative diseases. In summary, this PhD project has identified novel, innovative and realistic strategies that can be used in vitro to inhibit the functions exerted by the IGF-I:IGFBP:VN multiprotein complexes critical for cancer progression, with a potential to be translated into in vivo investigations. Furthermore, TF and SFN were found to mediate IGF-I:IGFBP:VN-induced effects, thereby revealing their potential to be used as therapeutic targets or as predictive biomarkers for the efficacy of IGF-1R targeting therapies in breast cancer patients. In addition to its therapeutic and clinical scope, this PhD project has significantly contributed to the understanding of the role of the IGF system in breast tumour biology by providing valuable new information on the mechanistic events underpinning IGF-I:VN-mediated effects on breast cell functions. Furthermore, this is the first instance where favourable binding sites for IGF-II, IGFBP-3 and IGFBP-5 on VN have been identified. Taken together, this study has functionally characterised the interactions between IGF-I and VN and through innovative strategies has provided a platform for the development of novel therapies targeting these interactions and their downstream effects.

Pharmacokinetics-based elucidation on disparity in clinical effectiveness between varieties of Zhi Zhu Wan, a traditional Chinese medical formula

AIM: Zhi Zhu Wan (ZZW) is a classical Chinese medical formulation used for the treatment of functional dyspepsia that attributed to Spleen-deficiency Syndrome. ZZW contains Atractylodes Rhizome and Fructus Citrus Immaturus, the later originates from both Citrus aurantium L. (BZZW) and Citrus sinensis Osbeck (RZZW). The present study is designed to elucidate disparities in the clinical efficacy of two ZZW varieties based on the pharmacokinetics of naringenin and hesperetin. MEHTOD: After oral administration of ZZWs, blood sample was collected from healthy volunteers at designed time points. Naringenin and hesperetin were detected in plasma by RP-HPLC, pharmacokinetic parameters were processed using mode-independent methods with WINNONLIN. RESULTS: After oral administration of BZZW, both naringenin and hesperetin were detected in plasma, and demonstrated similar pharmacokinetic parameters. Ka was 0.384+/-0.165 and 0.401+/-0.159, T(1/2(ke))(h) was 5.491+/-3.926 and 5.824+/-3.067, the AUC (mg/Lh) was 34.886+/-22.199 and 39.407+/-19.535 for naringenin and hesperetin, respectively. However, in the case of RZZW, only hesperetin was found in plasma, but the pharmacokinetic properties for hesperetin in RZZW was different from that in BZZW. T(max) for hesperetin in RZZW is about 8.515h, and its C(max) is much larger than that of BZZW. Moreover, it was eliminated slowly as it possessed a much larger AUC value. CONCLUSION: The distinct therapeutic orientations of the Chinese medical formula ZZWs with different Fructus Citrus Immaturus could be elucidated based on the pharmacokinetic parameters of constituents after oral administration.

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.

Association between migraine and a functional polymorphism at the dopamine β-hydroxylase locus

Migraine is a common neurological disorder with a significant genetic component. Although a number of linkage and association studies have been undertaken, the number and identity of all migraine susceptibility genes has yet to be defined. The existence of dopaminergic hypersensitivity in migraine has been recognised on a pharmacological basis and some studies have reported genetic association between migraine and dopamine-related gene variants. Our laboratory has previously reported association of migraine with a promoter STR marker in the dopamine beta hydroxylase (DBH) gene. In the present study, we analysed two additional DBH markers in two independent migraine case–control cohorts. These two markers are putative functional SNPs, one within the promoter (−1021C→T) and another SNP (+1603C→T) in exon 11 of the DBH gene. The results showed a significant association for allelic and genotypic frequency distribution between the DBH marker in the promoter and migraine in the first (P = 0.004 and P = 0.012, respectively) and the second (P = 0.013 and P = 0.031, respectively) tested cohorts. There was no association observed between either genotype and/or allelic frequencies for the DBH marker located in exon 11 and migraine (P ≥ 0.05). The promoter DBH marker, reported associated with migraine in this study, has been shown to affect up to 52% of plasma DBH activity. Varying DBH activity levels have been postulated to be involved in migraine process with an increase of dopamine, resulting from a lower DBH activity shown positively correlated with migraine severity. It is plausible that the functional promoter variant of DBH may play a role in the migraine disorder.

Association study of a functional variant in intron 8 of the dopamine transporter gene and migraine susceptibility

Migraine is a common, genetically influenced neurovascular disorder. The dopamine transporter gene is a candidate for migraine association studies. This study tested a functionally linked variable number tandem repeat (VNTR) in intron 8 of the dopamine transporter gene (DATInt8) in 550 migraine cases (401 with aura, 149 without aura) and 550 non-migraine controls. Chi-squared analysis of the DATInt8 revealed that the allele and genotype frequency distributions for migraine cases (including subtype analysis) and controls were not different (P > 0.1). These findings offer no evidence for an association of the DATInt8 with migraine with and without aura and therefore do not implicate the dopamine transporter gene as a modifier of migraine risk.

Discriminative ability of functional loading tests for adolescent jumper's knee

Objective. To investigate the reliability and validity of five squat-based loading tests that are clinically appropriate for jumper's knee. The loading tests were step up, double leg squat, double leg squat on a 25-degree decline (decline squat), single leg decline squat, and decline hop. Design. Cross-sectional controlled cohort. Subjects without knee pain comprised controls, those with extensor tendon pain comprised the jumper's knee group. Setting. Institutional athlete study group in Australia Participants. Fifty-six elite adolescent basketball players participated in this study, thirteen comprised the jumper's knee group, fifteen athletes formed a control group. Intervention. Each subject performed each loading test for baseline and reliability data on the first testing day. Subjects then performed three days of intensive (6 h daily) basketball training, after which each loading test was reexamined. Main outcome measures. Eleven point interval scale for pain. Results. The tests that best detected a change in pain due to intensive workload were the single leg decline squat and single leg decline hop. This study found that decline tests have better discriminative ability than the standard squat to detect change in jumper's knee pain due to intensive training. The typical error for these tests ranged from 0.3 to 0.5, however, caution should be exercised in the interpretation of these reliability figures due to relatively low scores. Conclusions. The single leg decline squat is recommended in the physical assessment of adolescent jumper's knee. The decline squat was selected as the best clinical test over the decline hop because it was easier to standardise performance.

NSAM-derived total surface area vs. SMPS-derived "mobility equivalent" surface area for different environmentally relevant aerosols

The surface area of inhaled particles deposited in the alveolar region, as reported by the TSI nanoparticle surface area monitor (NSAM), was compared with the corresponding value estimated by a TSI scanning mobility particle sizer (SMPS) for a range of environmentally relevant aerosols, including petrol emissions, ETS, laser printer emissions, cooking emissions and ambient aerosols. The SMPS values were based on a mobility size distribution assuming spherical particles using the appropriate size-dependent alveolar-deposition factors provided by the ICRP. In most cases, the two instruments showed good linear agreement. With petrol emissions and ETS, the linearity extended to over 103 μm2 cm-3. With printer emissions, there was good linearity up to about 300 μm2 cm-3 while the NSAM increasingly overestimated the surface area at higher concentrations. The presence of a nucleation event in ambient air caused the NSAM to over-estimate the surface area by a factor of 2. We summarize these results and conclude that the maximum number concentration up to which the NSAM is accurate clearly depends on the type of aerosol being sampled and provide guidance for the use of the instrument.

Prospective imaging study of asymptomatic patellar tendinopathy in elite junior basketball players

To evaluate the ability of ultrasonography to predict eventual symptoms in an at-risk population, 52 elite junior basketball players' patellar tendons were studied at baseline and again 16 months later. The group consisted of 10 study tendons (ultrasonographically hypoechoic at baseline) and 42 control tendons (ultrasonographically normal at baseline). By design, all tendons were asymptomatic at baseline. No differences were noted between subjects and controls at baseline for age, height, weight, training hours, and vertical jump. Functional (P < 0.01) and symptomatic outcome (P < 0.05) were poorer for subjects' tendons than for controls. Relative risk for developing symptoms of jumper's knee was 4.2 times greater in case tendons than in control tendons. Men were more likely to develop ultrasonographic changes than women (P < 0.025), and they also had significantly increased training hours per week (P < 0.01) in the study period. Half (50%) of abnormal tendons in women became ultrasonographically normal in the study period. Our data suggest that presence of an ultrasonographic hypoechoic area is associated with a greater risk of developing jumper's knee symptoms. Ultrasonographic patellar tendon changes may resolve, but this is not necessary for an athlete to become asymptomatic. Qualitative or quantitative analysis of baseline ultrasonographic images revealed it was not possible to predict which tendons would develop symptoms or resolve ultrasonographically.

Cost-effectiveness of a telephone-delivered education programme to prevent early childhood caries in a disadvantaged area : a cohort study

Objectives Early childhood caries is a highly destructive dental disease which is compounded by the need for young children to be treated under general anaesthesia. In Australia, there are long waiting periods for treatment at public hospitals. In this paper, we examined the costs and patient outcomes of a prevention programme for early childhood caries to assess its value for government services. Design Cost-effectiveness analysis using a Markov model. Setting Public dental patients in a low socioeconomic, socially disadvantaged area in the State of Queensland, Australia. Participants Children aged 6 months to 6 years received either a telephone prevention programme or usual care. Primary and secondary outcome measures A mathematical model was used to assess caries incidence and public dental treatment costs for a cohort of children. Healthcare costs, treatment probabilities and caries incidence were modelled from 6 months to 6 years of age based on trial data from mothers and their children who received either a telephone prevention programme or usual care. Sensitivity analyses were used to assess the robustness of the findings to uncertainty in the model estimates. Results By age 6 years, the telephone intervention programme had prevented an estimated 43 carious teeth and saved £69 984 in healthcare costs per 100 children. The results were sensitive to the cost of general anaesthesia (cost-savings range £36 043–£97 298) and the incidence of caries in the prevention group (cost-savings range £59 496–£83 368) and usual care (cost-savings range £46 833–£93 328), but there were cost savings in all scenarios. Conclusions A telephone intervention that aims to prevent early childhood caries is likely to generate considerable and immediate patient benefits and cost savings to the public dental health service in disadvantaged communities.

Does a functional activity programme improve function, quality of life, and falls for residents in long term care? Cluster randomised controlled trial

Objective To assess the effectiveness of an activity programme in improving function, quality of life, and falls in older people in residential care. Design Cluster randomised controlled trial with one year follow-up. Setting 41low level dependency residential carehomes in New Zealand. Participants 682 people aged 65 years or over. Interventions 330 residents were offered a goal setting and individualised activities of daily living activity programme by a gerontology nurse, reinforced by usual healthcare assistants; 352 residents received social visits. Main outcome measures Function (late life function and disability instruments, elderly mobility scale, FICSIT-4

Hydrothermally formed functional niobium oxide doped tungsten nanorods

Nanorod forms of metal oxides is recognised as one of the most remarkable morphologies. Their structure and functionality have driven important advancements in a vast range of electronic devices and applications. In this work, we postulate a novel concept to explain how numerous localised surface states can be engineered into the bandgap of niobium oxide nanorods using tungsten. We discuss their contributions as local state surface charges for the modulation of a Schottky barrier height, relative dielectric constant and their respective conduction mechanisms. Their effect on the hydrogen gas molecule interactions mechanisms are also examined herein. We synthesised niobium tungsten oxide (Nb17W2O25) nanorods via a hydrothermal growth method and evaluated the Schottky barrier height, ideality factor, dielectric constant and trap energy level from the measured I-V vs temperature characteristics in the presence of air and hydrogen to show the validity of our postulations.

Sensemaking and sustainable practicing: Functional affordances of information systems in green transformations

This paper explores how a world-wide operating software solutions provider implemented environmentally sustainable business practices in response to emerging environmental concerns. Through an interpretive case study, we develop a theoretical framework that identifies four important functional affordances originating in information systems, which are required in environmental sustainability transformations as they create an actionable context in which (1) organizations can engage in a sensemaking process related to understanding emerging environmental requirements, and (2) individuals can implement environmentally sustainable work practices. Through our work, we provide several contributions, including a better understanding of IS-enabled organizational change and the types of functional affordances of information systems that are required in sustainability transformations. We describe implications relating to (1) how information systems can contribute to the creation of environmentally sustainable organizations, (2) the design of information systems to create required functional affordances, (3) the management of sustainability transformations, and (4) the further development of the concept of functional affordances in IS research.