Association study of the calcitonin gene-related polypeptide-alpha (CALCA) and the receptor activity modifying 1 (RAMP1) genes with migraine

Migraine is a common neurovascular brain disorder characterised by recurrent attacks of severe headache that may be accompanied by various neurological symptoms. Migraine is thought to result from activation of the trigeminovascular system followed by vasodilation of pain-producing intracranial blood vessels and activation of second-order sensory neurons in the trigeminal nucleus caudalis. Calcitonin gene-related peptide (CGRP) is a mediator of neurogenic inflammation and the most powerful vasodilating neuropeptide, and has been implicated in migraine pathophysiology. Consequently, genes involved in CGRP synthesis or CGRP receptor genes may play a role in migraine and/or increase susceptibility. This study investigates whether variants in the gene that encodes CGRP, calcitonin-related polypeptide alpha (CALCA) or in the gene that encodes a component of its receptor, receptor activity modifying protein 1 (RAMP1), are associated with migraine pathogenesis and susceptibility. The single nucleotide polymorphisms (SNPs) rs3781719 and rs145837941 in the CALCA gene, and rs3754701 and rs7590387 at the RAMP1 locus, were analysed in an Australian Caucasian population of migraineurs and matched controls. Although we find no significant association of any of the SNPs tested with migraine overall, we detected a nominally significant association (p = 0.031) of the RAMP1 rs3754701 variant in male migraine subjects, although this is non-significant after Bonferroni correction for multiple testing.

Isolation of bioactive compounds that relate to the anti-platelet activity of Cymbopogon ambiguus

Infusions and decoctions of Cymbopogon ambiguus have been used traditionally in Australia for the treatment of headache, chest infections and muscle cramps. The aim of the present study was to screen and identify bioactive compounds from C. ambiguus that could explain this plant's anti-headache activity. A dichloromethane extract of C. ambiguus was identified as having activity in adenosine-diphosphate-induced human platelet aggregation and serotonin-release inhibition bioassays. Subsequent fractionation of this extract led to the isolation of four phenylpropenoids, eugenol, elemicin, Eugenol methylether and trans-isoelemicin. While both Eugenol and elemicin exhibited dose-dependent inhibition of ADP-induced human platelet serotonin release, only eugenol displayed potent inhibitory activity with an IC(50) value of 46.6 microM, in comparison to aspirin, with an IC(50) value of 46.1 microM. These findings provide evidence to support the therapeutic efficacy of C. ambiguus in the non-conventional treatment of Headache and Inflammatory conditions.

Home-based activity program for older people with depressive symptoms: DeLLITE–A randomized controlled trial

PURPOSE We wanted to assess the effectiveness of a home-based physical activity program, the Depression in Late Life Intervention Trial of Exercise (DeLLITE), in improving function, quality of life, and mood in older people with depressive symptoms. METHODS We undertook a randomized controlled trial involving 193 people aged 75 years and older with depressive symptoms at enrollment who were recruited from primary health care practices in Auckland, New Zealand. Participants received either an individualized physical activity program or social visits to control for the contact time of the activity intervention delivered over 6 months. Primary outcome measures were function, a short physical performance battery comprising balance and mobility, and the Nottingham Extended Activities of Daily Living scale. Secondary outcome measures were quality of life, the Medical Outcomes Study 36-item short form, mood, Geriatric Depression Scale (GDS-15), physical activity, Auckland Heart Study Physical Activity Questionnaire, and self-report of falls. Repeated measures analyses tested the differential impact on outcomes over 12 months’ follow-up. RESULTS The mean age of the participants was 81 years, and 59% were women. All participants scored in the at–risk category on the depression screen, 53% had a Diagnostic and Statistical Manual of Mental Disorders or International Classification of Diseases, Tenth Revision diagnosis of major depression or scored more than 4 on the GDS-15 at baseline, indicating moderate or severe depression. Almost all participants, 187 (97%), completed the trial. Overall there were no differences in the impact of the 2 interventions on outcomes. Mood and mental health related quality of life improved for both groups. CONCLUSION he DeLLITE activity program improved mood and quality of life for older people with depressive symptoms as much as the effect of social visits. Future social and activity interventions should be tested against a true usual care control.

Relative abundance of full-length and truncated FOXP1 isoforms is associated with differential NFκB activity in Follicular Lymphoma

FOXP1 is a transcriptional repressor that has been proposed to repress the expression of some NFκB-responsive genes. Furthermore, truncated forms of FOXP1 have been associated with a subtype of Diffuse Large B-cell Lymphoma characterised by constitutive NFκB activity, indicating that they may inhibit this repression. We have shown that FL tumors have increased relative abundance of truncated FOXP1 isoforms and this is associated with increased expression of NFκB-associated genes. Our results provide strong evidence that relative FOXP1 isoform abundance is associated with NFκB activity in FL, and could potentially be used as a marker for this gene signature.

PEGylation of lysine residues reduces the pro-migratory activity of IGF-I

Background: The insulin-like growth factor (IGF) system is composed of ligands and receptors which regulate cell proliferation, survival, differentiation and migration. Some functions are regulated via intracellular signaling cascades, others by involvement of the extracellular milieu, including binding proteins and other extracellular matrix proteins. However, understanding of their functions and the exact nature of these interactions remains incomplete. Methods: IGF-I was PEGylated at its lysine sites - K27, K65 and K68. Binding of PEG-IGF-I to the IGFBPs was analyzed using BIAcore and its ability to activate the IGF-IR was assessed using IGF-IR phosphorylation assay. Furthermore, functional consequences of PEGylating the lysine residues of IGF-I was investigated using cell viability and cell migration assays. In addition, particular downstream signaling pathways regularly implicated in these mechanisms were also dissected using phospho-AKT and phospho-ERK1/2 assays. Results: In this study, IGF-I specifically PEGylated at lysine 27 (PEG-K27), 65 (PEG-K65) or 68 (PEG-K68) were employed. Receptor phosphorylation was only reduced by 2-fold with PEG-K65 and PEG-K68 over all the time points tested, and as observed in two cell types, 3T3 fibroblasts and MCF-7 breast cancer cells. PEGylation at K27 resulted in a much larger effect, with more than 10-fold lower activation for 3T3 fibroblasts and a ~3 fold reduced IGF-IR activation for MCF-7 breast cancer cells over 15 minutes. In addition, all PEG-IGF-I variants demonstrated a ten-fold reduction in the association rate to IGF binding proteins (IGFBPs). Functionally, all PEG variants completely lost their ability to induce cell migration in the presence of IGFBP-3/vitronectin (VN) complexes as compared to IGF-I; in contrast, cell viability was fully preserved. Further investigations into the downstream signaling pathways revealed that the PI3-K/AKT pathway was preferentially affected upon treatment with the PEG-IGF-I variants compared to the MAPK/ERK pathway. Conclusion: PEGylation of IGF-I has an impact on cell migration but not cell viability. General significance: PEG-IGF-I may differentially modulate IGF-I mediated functions that are dependent on its interaction with its receptor as well as key extracellular proteins such as VN and IGFBPs.

Quantitative and qualitative changes in gene expression patterns characterize the activity of plaques in multiple sclerosis

Multiple sclerosis (MS) is a complex autoimmune disorder of the CNS with both genetic and environmental contributing factors. Clinical symptoms are broadly characterized by initial onset, and progressive debilitating neurological impairment. In this study, RNA from MS chronic active and MS acute lesions was extracted, and compared with patient matched normal white matter by fluorescent cDNA microarray hybridization analysis. This resulted in the identification of 139 genes that were differentially regulated in MS plaque tissue compared to normal tissue. Of these, 69 genes showed a common pattern of expression in the chronic active and acute plaque tissues investigated (Pvalue<0.0001, ρ=0.73, by Spearman's ρ analysis); while 70 transcripts were uniquely differentially expressed (≥1.5-fold) in either acute or chronic active tissues. These results included known markers of MS such as the myelin basic protein (MBP) and glutathione S-transferase (GST) M1, nerve growth factors, such as nerve injury-induced protein 1 (NINJ1), X-ray and excision DNA repair factors (XRCC9 and ERCC5) and X-linked genes such as the ribosomal protein, RPS4X. Primers were then designed for seven array-selected genes, including transferrin (TF), superoxide dismutase 1 (SOD1), glutathione peroxidase 1 (GPX1), GSTP1, crystallin, alpha-B (CRYAB), phosphomannomutase 1 (PMM1) and tubulin β-5 (TBB5), and real time quantitative (Q)-PCR analysis was performed. The results of comparative Q-PCR analysis correlated significantly with those obtained by array analysis (r=0.75, Pvalue<0.01, by Pearson's bivariate correlation). Both chronic active and acute plaques shared the majority of factors identified suggesting that quantitative, rather than gross qualitative differences in gene expression pattern may define the progression from acute to chronic active plaques in MS.

Illustrating outcomes for Australian nascent and young firm entrepreneurial activity

This paper examines the outcomes of nascent and young entrepreneurial firms in Australia. Findings of interest in this paper include: • After three years similar proportions of nascent firms reach an operational state (31 per cent), i.e. sales regularly exceed costs, compared with those that have terminated (35 per cent), and those who are still trying to achieve venture creation (34 per cent). This outcome closely mirrors the outcomes in the US PSED study. • The young firm sample shows that these new ventures remain more robust to firm closure. The vast majority of young firms (78 per cent) continue to be active in the market the last time they participated in CAUSEE. • The annual termination rate for young firms is 9 per cent at most, and 14 per cent cumulatively, while cumulatively only 8 per cent of young firms experience a drop-off in activity to be considered as having uncertain status. • The average number of employees in Nascent Firms is one person, the average number of Young Firm employees increases from two at first sampling to three after three years. • While the founders of exiting Nascent Firms are more likely to return to their old job upon termination of their business, Young Firm founders move on to new jobs. Regardless the majority of exiting firm founders rate their experience as positive and are prepared to attempt business creation in the future.

Personal exposure to ultrafine particles : the influence of time-activity patterns

Exposure to ultrafine particles (UFPs) is deemed to be a major risk affecting human health. Therefore, airborne particle studies were performed in the recent years to evaluate the most critical micro-environments, as well as identifying the main UFP sources. Nonetheless, in order to properly evaluate the UFP exposure, personal monitoring is required as the only way to relate particle exposure levels to the activities performed and micro-environments visited. To this purpose, in the present work, the results of experimental analysis aimed at showing the effect of the time-activity patterns on UFP personal exposure are reported. In particular, 24 non-smoking couples (12 during winter and summer time, respectively), comprised of a man who worked full-time and a woman who was a homemaker, were analyzed using personal particle counter and GPS monitors. Each couple was investigated for a 48-h period, during which they also filled out a diary reporting the daily activities performed. Time activity patterns, particle number concentration exposure and the related dose received by the participants, in terms of particle alveolar-deposited surface area, were measured. The average exposure to particle number concentration was higher for women during both summer and winter (Summer: women 1.8×104 part. cm-3; men 9.2×103 part. cm-3; Winter: women 2.9×104 part. cm-3; men 1.3×104 part. cm-3), which was likely due to the time spent undertaking cooking activities. Staying indoors after cooking also led to higher alveolar-deposited surface area dose for both women and men during the winter time (9.12×102 and 6.33×102 mm2, respectively), when indoor ventilation was greatly reduced. The effect of cooking activities was also detected in terms of women’s dose intensity (dose per unit time), being 8.6 and 6.6 in winter and summer, respectively. On the contrary, the highest dose intensity activity for men was time spent using transportation (2.8 in both winter and summer).

Using cultural-historical activity theory (CHAT) to study the relationship between school leadership and organisational change

This study aimed to identify how school leaders’ practices influence department activities during school transformation. The method used to explore emerging disturbances and contradictions within and between school departments was based on Cultural Historical Activity Theory (CHAT). The findings show that in order to implement educational changes in schools successfully, leaders should promote the change they envision as being highly consistent with the current collective identity (shared object) of the departments. From this perspective, the systemic components of the school departments are given a sense of preservation and continuity, rather than loss.

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

Quality of life, fatigue and activity in Australians with chronic kidney disease : a longitudinal study

Aims and objectives This study sought to determine the relationship between health related quality of life (HRQoL), fatigue and activity levels of people with anaemia secondary to chronic kidney disease (CKD) over a 12 month period following the introduction of an erythropoietin stimulating agent (ESA). Background CKD occurs in five stages and it is a complex chronic illness which severely impacts on an individual’s HRQoL, and ability to perform everyday activities. Fatigue is also a common symptom experienced by people with CKD. Design and methods Using a longitudinal repeated measures design, 28 people with CKD completed the SF-36, human activity profile and fatigue severity scale at the commencement of an ESA and then at 3, 6 and 12 months. Results Over a 12 month period, people reported a significant change in HRQoL in relation to role physical, vitality, mental health/emotional well-being and overall mental health. However activity levels did not significantly improve during that time. Both the amount of breathlessness and level of fatigue were highest at baseline and declined over time. Both fatigue and breathlessness were correlated with less reported general health over time. Conclusion Renal nurses, in dialysis units and CKD outpatient clinics, have repeated and frequent contact with people with CKD over long periods of time, and are in an ideal position to routinely assess fatigue and activity levels and to institute timely interventions. Early detection would enable timely nursing interventions to optimise HRQoL and independent activity. Relevance to Clinical Practice Drawing on rehabilitation nursing interventions could assist renal nurses to minimize the burden of fatigue and its impact on simple everyday activities and a person’s quality of life. These interventions are important for people who are living at home and could assist in lowering the burden on home support services.

Relationship of moderate and low isometric lumbar extension through architectural and muscular activity variables: a cross sectional study

Background No study relating the changes obtained in the architecture of erector spinae (ES) muscle were registered with ultrasound and different intensities of muscle contraction recorded by surface EMG (electromyography) on the ES muscle was found. The aim of this study was analyse the relationship in the response of the ES muscle during isometric moderate and light lumbar isometric extension considering architecture and functional muscle variables. Methods Cross-sectional study. 46 subjects (52% men) with a group mean age of 30.4 (±7.78). The participants developed isometric lumbar extension while performing moderate and low isometric trunk and hip extension in a sitting position with hips flexed 90 degrees and the lumbar spine in neutral position. During these measurements, electromyography recordings and ultrasound images were taken bilaterally. Bilaterally pennation angle, muscle thickness, torque and muscle activation were measured. This study was developed at the human movement analysis laboratory of the Health Science Faculty of the University of Malaga (Spain). Results Strong and moderate correlations were found at moderate and low intensities contraction between the variable of the same intensity, with correlation values ranging from 0.726 (Torque Moderate – EMG Left Moderate) to 0.923 (Angle Left Light – Angle Right Light) (p < 0.001). This correlation is observed between the variables that describe the same intensity of contraction, showing a poor correlation between variables of different intensities. Conclusion There is a strong relationship between architecture and function variables of ES muscle when describe an isometric lumbar extension at light or moderate intensity. Keywords: Ultrasonography; Surface electromyography; Thickness; Pennation angle; Erector spinae

An androgen receptor mutation in the MDA-MB-453 cell line model of molecular apocrine breast cancer compromises receptor activity

Recent evidence indicates that the estrogen receptor-a-negative, androgen receptor (AR)- positive molecular apocrine subtype of breast cancer is driven by AR signaling. The MDA-MB-453 cell line is the prototypical model of this breast cancer subtype; its proliferation is stimulated by androgens such as 5a-dihydrotestosterone (DHT) but inhibited by the progestin medroxyprogesterone acetate (MPA) via AR-mediated mechanisms. We report here that the AR gene in MDAMB- 453 cells contains a G-T transversion in exon 7, resulting in a receptor variant with a glutamine to histidine substitution at amino acid 865 (Q865H) in the ligand binding domain. Compared with wild-type AR, the Q865H variant exhibited reduced sensitivity to DHT and MPA in transactivation assays in MDA-MB-453 and PC-3 cells but did not respond to non-androgenic ligands or receptor antagonists. Ligand binding, molecular modeling, mammalian two-hybrid and immunoblot assays revealed effects of the Q865H mutation on ligand dissociation, AR intramolecular interactions, and receptor stability. Microarray expression profiling demonstrated that DHT and MPA regulate distinct transcriptional programs in MDA-MB-453 cells. Gene Set Enrichment Analysis revealed that DHT- but not MPA-regulated genes were associated with estrogen-responsive transcriptomes from MCF-7 cells and the Wnt signaling pathway. These findings suggest that the divergent proliferative responses of MDA-MB-453 cells to DHT and MPA result from the different genetic programs elicited by these two ligands through the AR-Q865H variant. This work highlights the necessity to characterize additional models of molecular apocrine breast cancer to determine the precise role of AR signaling in this breast cancer subtype. Endocrine-Related Cancer (2012) 19 599–613

Cone signals and activity in myopia and emmetropia

Myopia (short-sightedness) is a common ocular disorder of children and young adults. Studies primarily using animal models have shown that the retina controls eye growth and the outer retina is likely to have a key role. One theory is that the proportion of L (long-wavelength-sensitive) and M (medium-wavelength-sensitive) cones is related to myopia development; with a high L/M cone ratio predisposing individuals to myopia. However, not all dichromats (persons with red-green colour vision deficiency) with extreme L/M cone ratios have high refractive errors. We predict that the L/M cone ratio will vary in individuals with normal trichromatic colour vision but not show a systematic difference simply due to refractive error. The aim of this study was to determine if L/M cone ratios in the central 30° are different between myopic and emmetropic young, colour normal adults. Information about L/M cone ratios was determined using the multifocal visual evoked potential (mfVEP). The mfVEP can be used to measure the response of visual cortex to different visual stimuli. The visual stimuli were generated and measurements performed using the Visual Evoked Response Imaging System (VERIS 5.1). The mfVEP was measured when the L and M cone systems were separately stimulated using the method of silent substitution. The method of silent substitution alters the output of three primary lights, each with physically different spectral distributions to control the excitation of one or more photoreceptor classes without changing the excitation of the unmodulated photoreceptor classes. The stimulus was a dartboard array subtending 30° horizontally and 30° vertically on a calibrated LCD screen. The m-sequence of the stimulus was 215-1. The N1-P1 amplitude ratio of the mfVEP was used to estimate the L/M cone ratio. Data were collected for 30 young adults (22 to 33 years of age), consisting of 10 emmetropes (+0.3±0.4 D) and 20 myopes (–3.4±1.7 D). The stimulus and analysis techniques were confirmed using responses of two dichromats. For the entire participant group, the estimated central L/M cone ratios ranged from 0.56 to 1.80 in the central 3°-13° diameter ring and from 0.94 to 1.91 in the more peripheral 13°-30° diameter ring. Within 3°-13°, the mean L/M cone ratio of the emmetropic group was 1.20±0.33 and the mean was similar, 1.20±0.26, for the myopic group. For the 13°-30° ring, the mean L/M cone ratio of the emmetropic group was 1.48±0.27 and it was slightly lower in the myopic group, 1.30±0.27. Independent-samples t-test indicated no significant difference between the L/M cone ratios of the emmetropic and myopic group for either the central 3°-13° ring (p=0.986) or the more peripheral 13°-30° ring (p=0.108). The similar distributions of estimated L/M cone ratios in the sample of emmetropes and myopes indicates that there is likely to be no association between the L/M cone ratio and refractive error in humans.