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PURPOSE: This study examines the associations between migraine headaches, well-being, and health care use among a sample of underserved older African American adults. Controlling for relevant variables, the association between migraine headaches and (1) health care utilization, (2) health-related quality of life (HRQoL), and (3) physical and mental health outcomes was examined. METHODS: Our sample included 760 older African American adults from South Los Angeles recruited through convenience and snowball sampling. In addition to demographic variables, our survey included validated instruments, such as the SF-12 QoL, Short-Form McGill Pain Questionnaire, and the Geriatric Depression Scale. Data analysis included 12 independent multivariate models using multiple linear regression, log transferred linear regression, binary and multinomial logistic regression, and generalized linear regression with Poisson distribution. RESULTS: Having migraine was associated with three categories of outcomes: (1) higher level of health care utilization measured by (i) emergency department admissions and (ii) number of medication use; (2) lower level of HRQoL and health status measured by (i) lower self-rated health (ii) physical QoL, and (iii) mental QoL; and (3) worse physical and mental health outcomes measured by (i) higher number of depressive symptoms, (ii) higher level of pain, (iii) sleep disorder, and (iv) being disabled. CONCLUSIONS: Migraine headache significantly was associated with quality of life, health care utilization, and many health outcomes of underserved African American middle-aged and older adults. Diagnoses and treatments of migraine among underserved older African American adults require multi-faceted and culturally sensitive interventional studies.

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Hydrophobicity has proven to be an extremely useful parameter in small molecule drug discovery programmes given that it can be used as a predictive tool to enable rational design. For larger molecules, including peptoids, where folding is possible, the situation is more complicated and the average hydrophobicity (as determined by RP-HPLC retention time) may not always provide an effective predictive tool for rational design. Herein, we report the first ever application of partitioning experiments to determine the log D values for a series of peptoids. By comparing log D and average hydrophobicities we highlight the potential advantage of employing the former as a predictive tool in the rational design of biologically active peptoids.

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Peptoids are a promising class of antimicrobial agents with reported activities against a range of both Gram-positive and Gram-negative bacteria, fungi and most recently parasites. However, at present the available toxicity data is somewhat limited and as such rationally designing effective antimicrobial peptoids can be challenging. Herein, we present the toxicity profiling of a series of linear peptoids against mammalian cell lines (HaCaT and HepG2). The cytotoxicity of the peptoid library has then been correlated with their antibacterial properties against Gram-positive and Gram-negative bacteria and also to the hydrophobicity of the peptoid sequences. The work presented provides valuable data to aid in the future rational design of antimicrobial peptoids.

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Herein we report a practical synthetic route to the lasso peptide lassomycin () and C-terminal variant lassomycin-amide (). The biological evaluation of peptides and against Mycobacterium tuberculosis revealed that neither had any activity against this bacterium. This lack of biological activity has led us to propose that naturally occurring lassomycin may actually exhibit a standard lasso peptide threaded conformation rather than the previously reported unthreaded structure.

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Peptoids are a promising class of peptidomimetics that exhibit the key chemical and physical properties of peptides but without being hampered by susceptibility towards enzymatic degradation. Biologically active peptoids are often designed to be amphipathic in nature, consisting of hydrophobic monomers interspersed with either cationic lysine-type or arginine-type monomers. Access to amphipathic peptoids that contain both lysine-type and arginine-type monomers is highly desirable as it offers a route to further modulate the biological properties of this class of molecule. However, the lack of a suitable synthetic route to prepare mixed cationic peptoids has meant that their biological potential has remained almost largely unexplored. Herein, we present an efficient synthetic route that can be used to access novel cationic peptoids containing both lysine-type and arginine-type monomers within the same sequence.

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Twelve avian diseases are listed by the World Organisation for Animal Health (OIE), although more than 100 infectious diseases have been described in commercial poultry. This article summarises a recent assessment of the biosecurity risks posed by non-listed avian diseases associated with imports of chilled or frozen chicken meat and meat products into New Zealand. Following the guidelines described in Chapter 2.1 of the OIE Terrestrial Animal Health Code, avian adenovirus splenomegaly virus, avian paramyxovirus-2 (APMV-2), Bordetella avium, Mycoplasma spp., Ureaplasma spp., Ornithobacterium rhinotracheale, Riemerella anatipestifer, and Salmonella arizonae have been identified as hazards. However, of all the non-listed avian diseases discussed here, only APMV-2 and S. arizonae are assessed as being risks associated with the commercial import of chicken meat into New Zealand. Specific control measures may have to be implemented to mitigate such risks. This conclusion is likely to reflect both the high-health status of New Zealand poultry and the threat posed by these infectious agents to New Zealand's unique population of native psittacine species.

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A quantitative model was developed to estimate the likelihood of an incursion of porcine reproductive and respiratory syndrome virus (PRRSV) into New Zealand through the importation of fresh consumer-ready cuts of pig meat. A sensitivity analysis of all the inputs used in this model illustrated the importance of correctly modelling the available 'dose-response' data, and a mechanistic Beta-Poisson model was shown to be the most appropriate method for this in the authors' assessment. The output of this model predicts an average of approximately 1,200 years between PRRSV introductions resulting in primary infections in New Zealand. Given the uncertainties in the model, there is 95% confidence that this time period ranges from 52 to 6,200 years. The values chosen in this model are considered to provide a conservative estimate of the likelihood of introducing PRRSV into New Zealand via the importation of fresh pork.

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PURPOSE: A computer-based interactive binocular treatment system (I-BiT) for amblyopia has been developed, which utilises commercially available 3D 'shutter glasses'. The purpose of this pilot study was to report the effect of treatment on visual acuity (VA) in children with amblyopia. METHODS: Thirty minutes of I-BiT treatment was given once weekly for 6 weeks. Treatment sessions consisted of playing a computer game and watching a DVD through the I-BiT system. VA was assessed at baseline, mid-treatment, at the end of treatment, and at 4 weeks post treatment. Standard summary statistics and an exploratory one-way analysis of variance (ANOVA) were performed. RESULTS: Ten patients were enrolled with strabismic, anisometropic, or mixed amblyopia. The mean age was 5.4 years. Nine patients (90%) completed the full course of I-BiT treatment with a mean improvement of 0.18 (SD=0.143). Six out of nine patients (67%) who completed the treatment showed a clinically significant improvement of 0.125 LogMAR units or more at follow-up. The exploratory one-way ANOVA showed an overall effect over time (F=7.95, P=0.01). No adverse effects were reported. CONCLUSION: This small, uncontrolled study has shown VA gains with 3 hours of I-BiT treatment. Although it is recognised that this pilot study had significant limitations-it was unblinded, uncontrolled, and too small to permit formal statistical analysis-these results suggest that further investigation of I-BiT treatment is worthwhile.

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Rett syndrome (RTT) is a disorder with a pronounced neurological phenotype and is caused mainly by mutations in the X-linked gene MECP2. A common feature of RTT is an abnormal electroencephalography and a propensity for seizures. In the current study we aimed to assess brain network excitability and seizure propensity in a mouse model of RTT. Mice in which Mecp2 expression was silenced (Mecp2(stop/y)) showed a higher seizure score (mean=6 ± 0.8 compared to 4±0.2 in wild-type [WT]) and more rapid seizure onset (median onset=10 min in Mecp2(stop/y) and 32 min in WT) when challenged with the convulsant drug kainic acid (25mg/kg). Hippocampal slices from Mecp2(stop/y) brain displayed no spontaneous field potential activities under control conditions but showed higher power gamma frequency field potential oscillations compared to WT in response to kainic acid (400 nM) in vitro. Brain slices challenged with the GABA(A)-receptor antagonist bicuculline (0.1-10 µM) and the potassium channel blocker 4-aminopyridine (1-50 µM) also revealed differences between genotypes with hippocampal circuits from Mecp2(stop/y) mouse slices showing enhanced epileptiform burst duration and frequency. In contrast to these network level findings, single cell analysis of pyramidal cells by whole-cell patch clamp recording revealed no detectable differences in synaptic or biophysical properties between methyl-CpG-binding protein 2 (MeCP2)-containing and MeCP2-deficient neurons. These data support the proposal that loss of MeCP2 alters network level excitability in the brain to promote epileptogenesis.

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The study was undertaken to investigate the effects of pacing on aspects of performance at an assembly task and on the operators' responses related to work behaviour, perceived workload and perceived stress. A particular objective of the study was to investigate whether physical and cognitive demands may interact in their influences on these effects. An assembly task was simulated in the laboratory and the level of pacing imposed, work height and memory load within the task were all varied. The results showed that the type of pacing commonly imposed (as is common with a lean manufacturing Takt time system in industry) can significantly affect both performance and perceived workload and stress. Physical demands (through work height affecting posture) and mental demand (through memory load) were also found to have significant effects, as would be expected from the many studies of these in the literature. More importantly, some interactions were found between pacing and work height in their effects on quality of assembly and the operator's own rating of performance, and between work height and memory load in their effects on errors. These findings will need to be taken into account by companies when implementing Takt time systems.

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A number of animal diseases can be transmitted to pigs via meat if the animals are fed scraps of meat imported from infected countries. For this reason, garbage feeding of pigs is regulated in many countries. The major porcine diseases recognised as being significant for this transmission pathway are foot and mouth disease, African swine fever, classical swine fever and swine vesicular disease. The World Organisation for Animal Health Terrestrial Animal Health Code (the Terrestrial Code) offers risk management recommendations for meat from countries where these diseases are present. However, there is no Terrestrial Code chapter on porcine reproductive and respiratory syndrome (PRRS), a relatively new viral disease of pigs which, since its recognition in the 1990s, has become endemic in most pig-producing countries. This paper assesses the risk of spread of PRRS virus through trade in pig meat, and concludes that the likelihood of its transmission by this pathway is negligible.

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Increasing international trade in poultry meat presents an opportunity for the global dissemination of poultry disease. However, it would be very unfortunate if expanding world trade resulted in animal diseases being used as unjustified non-tariff trade barriers. For those avian diseases currently listed by the World Organisation for Animal Health, the current evidence suggests that only highly pathogenic avian influenza, Newcastle disease, and (for chicken meat) infectious bursal disease should be considered likely to be spread though trade in this commodity.

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The international trade in poultry hatching eggs could potentially facilitate the global dissemination of poultry disease. Provided the guidelines of the World Organisation for Animal Health (OIE) on breeding flock hygiene are followed, of those avian diseases currently listed by the OlE, only highly pathogenic avian influenza (HPAI), Newcastle disease (ND), and avian mycoplasmosis (caused by Mycoplasma gallisepticum or M. synoviae) should be considered likely to be spread though trade in this commodity. Furthermore, the impact of HPAI and ND on egg production and hatchability will constrain the potential for these agents to be spread by poultry hatching eggs.

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BACKGROUND AND PURPOSE: Proteinase-activated receptor-2 (PAR2) is widely expressed in the CNS under normal physiological conditions. However, its potential role in modulating neuronal excitability and synaptic transmission remains to be determined. Here, we have investigated whether PAR2 activation modulates synaptic activity in the hippocampus. EXPERIMENTAL APPROACH: PAR2 activation and its effect on the hippocampus were examined in rat primary cultures and acute slices using whole cell patch clamp and standard extracellular recordings, respectively. KEY RESULTS: PAR2 activation leads to a depolarization of hippocampal neurones and a paradoxical reduction in the occurrence of synaptically driven spontaneous action potentials (APs). PAR2-induced neuronal depolarization was abolished following either the inhibition of astrocytic function or antagonism of ionotropic glutamate receptors whilst the PAR2-induced decrease in AP frequency was also reduced when astrocytic function was inhibited. Furthermore, when examined in acute hippocampal slices, PAR2 activation induced a profound long-term depression of synaptic transmission that was dependent on NMDA receptor activation and was sensitive to disruption of astrocytic function. CONCLUSIONS AND IMPLICATIONS: These novel findings show that PAR2 activation indirectly inhibits hippocampal synaptic activity and indicate that these receptors may play an active role in modulating normal physiological CNS function, in addition to their role in pathophysiological disorders.

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Rett syndrome (RTT), a disorder caused almost exclusively by mutations in the X-linked gene, MECP2, has a phenotype thought to be primarily of neurological origin. Disruption of Mecp2 in mice results in a prominent RTT-like phenotype. One of the consequences of MeCP2 absence in the brain is altered functional and structural plasticity. We aimed to characterize synaptic effects related to plasticity in the hippocampus further and establish whether plasticity defects are amenable to pharmacological reversal. Using male mice in which Mecp2 expression was prevented by a stop cassette, we assessed synaptic plasticity in area CA1 at different phenotypic stages, scoring the mice weekly for overt RTT-like signs. Strongly symptomatic Mecp2(stop/y) mice displayed reduced long-term potentiation (LTP, 40.2±1.6% of wild-type), post-tetanic potentiation (PTP, 45±18.8% of wild-type) and paired-pulse facilitation (PPF, 78±0.1% of wild type) (all P<0.05), the impairment increasing with symptom severity score. These plasticity impairments were absent in presymptomatic mice. Repeated high frequency stimulation revealed pronounced LTP saturation in symptomatic Mecp2(stop/y) mice, suggesting an LTP 'ceiling' effect. Bath application of the weak NMDA receptor blocker memantine (1 µM) resulted in partial restoration of a short-term plasticity component. These data support that idea that progressive functional synaptic impairment is a key feature in the RTT brain and demonstrate the potential for the pharmacological restoration of plasticity function.

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BACKGROUND AND PURPOSE: Recent evidence suggests that variation in the SNCA, MAPT, and GSK3B genes interacts in affecting risk for Parkinson disease (PD). In the current study, we attempt to validate previously published findings, evaluating gene-gene interactions between SNCA, MAPT, and GSK3B in association with PD. METHODS: Three Caucasian PD patient-control series from the United States, Ireland, and Norway (combined n = 1020 patients and 1095 controls) were genotyped for SNCA rs356219, MAPT H1/H2-discriminating SNP rs1052553, and GSK3B rs334558 and rs6438552. RESULTS: Our findings indicate that as previously reported, the SNCA rs356219-G allele and MAPT rs1052553 (H1 haplotype) were both associated with an increased risk of PD, whilst contrary to previous reports, GSK3B variants were not. No pair-wise interaction was observed between SNCA, MAPT, and GSK3B; the risk effects of SNCA rs356219-G and MAPT rs1052553-H1 were seen in a similar manner across genotypes of other variants, with no evidence suggesting synergistic, antagonistic, or deferential effects. CONCLUSIONS: In the Caucasian patient-control series examined, risk for PD was influenced by variation in SNCA and MAPT but not GSK3B. Additionally, those three genes did not interact in determining disease risk.

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Finite element analysis (FEA) is a fundamental method to study stresses and strains in complex structures, with the accuracy of an FEA being reliant on a number of variables, not least the precision and complexity of the model's geometry. Techniques such as computed tomography (CT) allow general geometries to be derived relatively quickly; however, constraints on CT image resolution mean defining subcortical geometries can be problematic. In relation to the overall mechanical response of a complex structure during FEA, the consequence of variable subcortical modelling is not known. Here we test this sensitivity with a series of FE models of a macaque mandible with different subcortical geometries and comparing the FEA strain magnitudes and orientations. The validity of the FE models was tested by carrying out experimental strain measurements on the same mandible. These strain measurements matched the FE predictions, providing confidence that material properties and model geometry were suitably defined. Results of this study show that cortical bone alone is not as effective in resisting bending as it is when coupled with subcortical bone, and as such subcortical geometries must be modelled during an FEA. This study demonstrates that the fine detail of the mandibular subcortical structure can be adequately modelled as a solid when assigned an appropriate Young's modulus value, in this case ranging from 1 to 2 GPa. This is an important and encouraging result for the creation of FE models of materials where CT image resolution or poor preservation prevent the accurate modelling of subcortical bone.

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BACKGROUND AND PURPOSE: Whilst an association between the tau gene (MAPT)-containing H1 haplotype and supranuclear gaze palsy (PSP) has long been recognized, the effect of H1 on risk for Parkinson's disease (PD) has remained more contentious. METHODS: Herein, we examined the association of H1 and PD in three Caucasian PD patient-control series from Ireland, Norway, and the US (combined: n = 2619), by genotyping two H1/H2 single nucleotide polymorphisms (SNPs) in MAPT (rs1052553) and in the Saitohin gene (rs62063857) and one H1-specific SNP (rs242557). RESULTS: We identified a significant association between H1/H2 and risk of PD (rs1052553 OR: 1.43, CI: 1.23-1.64; rs62063857 OR: 1.45, CI: 1.27-1.67), but no effect of the H1-specific SNP rs242557 (OR: 0.92, CI: 0.82-1.03). CONCLUSIONS: Our findings show that the H1 haplotype is a significant risk factor for PD. However, one H1-specific SNP (rs242557) previously implicated in PSP did not alter the risk of PD, indicating that distinct H1 sub-haplotypes probably drive the associations with PD and PSP.

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OBJECTIVE: Recently, mutations in DCTN1 were found to cause Perry syndrome, a parkinsonian disorder with TDP-43-positive pathology. Previously, mutations in DCTN1 were identified in a family with lower motor neuron disease, in amyotrophic lateral sclerosis (ALS), and in a family with ALS/frontotemporal dementia (FTD), suggesting a central role for DCTN1 in neurodegeneration. METHODS: In this study we sequenced all DCTN1 exons and exon-intron boundaries in 286 samples diagnosed with Parkinson disease (PD), frontotemporal lobar degeneration (FTLD), or ALS. RESULTS: This analysis revealed 36 novel variants (9 missense, 5 silent, and 22 noncoding). Segregation analysis in families and association studies in PD, FTLD, and ALS case-control series did not identify any variants segregating with disease or associated with increased disease risk. CONCLUSIONS: This study suggests that pathogenic mutations in DCTN1 are rare and do not play a common role in the development of Parkinson disease, frontotemporal lobar degeneration, or amyotrophic lateral sclerosis.

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OBJECTIVE: To report the study of a multigenerational Swiss family with dopa-responsive dystonia (DRD). METHODS: Clinical investigation was made of available family members, including historical and chart reviews. Subject examinations were video recorded. Genetic analysis included a genome-wide linkage study with microsatellite markers (STR), GTP cyclohydrolase I (GCH1) gene sequencing, and dosage analysis. RESULTS: We evaluated 32 individuals, of whom 6 were clinically diagnosed with DRD, with childhood-onset progressive foot dystonia, later generalizing, followed by parkinsonism in the two older patients. The response to levodopa was very good. Two additional patients had late onset dopa-responsive parkinsonism. Three other subjects had DRD symptoms on historical grounds. We found suggestive linkage to the previously reported DYT14 locus, which excluded GCH1. However, further study with more stringent criteria for disease status attribution showed linkage to a larger region, which included GCH1. No mutation was found in GCH1 by gene sequencing but dosage methods identified a novel heterozygous deletion of exons 3 to 6 of GCH1. The mutation was found in seven subjects. One of the patients with dystonia represented a phenocopy. CONCLUSIONS: This study rules out the previously reported DYT14 locus as a cause of disease, as a novel multiexonic deletion was identified in GCH1. This work highlights the necessity of an accurate clinical diagnosis in linkage studies as well as the need for appropriate allele frequencies, penetrance, and phenocopy estimates. Comprehensive sequencing and dosage analysis of known genes is recommended prior to genome-wide linkage analysis.

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