Centipede venoms as a source of drug leads

peerreview_statement: The publishing and review policy for this title is described in its Aims & Scope. aims_and_scope_url: http://www.tandfonline.com/action/journalInformation?show=aimsScope&journalCode=iedc20© 2016 Taylor and Francis. The attached document is the authors' final submitted version of the journal article. You are advised to consult the publisher's version if you wish to cite from it

Alcohol use disorders and risk of Parkinson’s disease: findings from a Swedish national cohort study 1972–2008

BACKGROUND: Alcohol has been suggested to be either protective of, or not associated with Parkinson’s disease (PD). However, experimental animal studies indicate that chronic heavy alcohol consumption may have dopamine neurotoxic effects relevant for PD. We studied the association between diagnosed alcohol use disorders and PD. METHODS: All individuals in Sweden admitted with a diagnosis of an alcohol use disorder or appendicitis (reference group) between January 1, 1972 and December 31, 2008 were identified through the Swedish National Inpatient Register, and followed for up to 37 years for a diagnosis of PD. We estimated hazard ratios (HR) with 95% confidence intervals (CI) and adjusted for age and sex. RESULTS: We found 1,741 (0.3%) cases of PD in the cohort of 602,930 individuals, 1,083 (0.4%) among those admitted with an alcohol use disorder and 658 (0.2%) of the individuals admitted with appendicitis. The mean follow-up time was 13.6 and 17.1 years, respectively. The HR for PD associated with an alcohol use disorder was 1.38 (CI 1.25-1.53) adjusted for age and sex. When the risk was estimated in age groups for first hospital admission with PD the highest risk was observed in the lowest age group, ≤44, HR 2.39 (0.96-5.93), adjusted for age at exposure and sex. CONCLUSIONS: A history of an alcohol use disorder conferred an increased risk of admission with a diagnosis of Parkinson’s disease in both women and men. In particular, the risk seemed higher at lower ages of first admission with Parkinson’s disease

Symptoms of Anxiety and Cardiac Hospitalizations at 12 Months in Patients with Heart Failure

OBJECTIVE: Heart failure (HF) is a leading cause of hospitalization. Clinical and socio-demographic factors have been associated with cardiac admissions, but little is known about the role of anxiety. We examined whether symptoms of anxiety were associated with cardiac hospitalizations at 12 months in HF patients. METHODS: HF outpatients (N=237) completed the Hospital Anxiety and Depression Scale (HADS) at baseline (i.e., inclusion into the study). A cutoff ≥8 was used to indicate probable clinical levels of anxiety and depression. At 12 months, a medical chart abstraction was performed to obtain information on cardiac hospitalizations. RESULTS: The prevalence of symptoms of anxiety was 24.9 % (59/237), and 27.0 % (64/237) of patients were admitted for cardiac reasons at least once during the 12-month follow-up period. Symptoms of anxiety were neither significantly associated with cardiac hospitalizations in univariable logistic analysis [OR=1.13, 95% CI (0.59–2.17), p=0.72] nor in multivariable analysi

Factors influencing psychological distress during a disease epidemic: Data from Australia's first outbreak of equine influenza

BACKGROUND: In 2007 Australia experienced its first outbreak of highly infectious equine influenza. Government disease control measures were put in place to control, contain, and eradicate the disease; these measures included movement restrictions and quarantining of properties. This study was conducted to assess the psycho-social impacts of this disease, and this paper reports the prevalence of, and factors influencing, psychological distress during this outbreak. METHODS: Data were collected using an online survey, with a link directed to the affected population via a number of industry groups. Psychological distress, as determined by the Kessler 10 Psychological Distress Scale, was the main outcome measure. RESULTS: In total, 2760 people participated in this study. Extremely high levels of non-specific psychological distress were reported by respondents in this study, with 34% reporting high psychological distress (K10 > 22), compared to levels of around 12% in the Australian general population. Analysis, using backward stepwise binary logistic regression analysis, revealed that those living in high risk infection (red) zones (OR = 2.00; 95% CI: 1.57-2.55; p < 0.001) and disease buffer (amber) zones (OR = 1.83; 95% CI: 1.36-2.46; p < 0.001) were at much greater risk of high psychological distress than those living in uninfected (white zones). Although prevalence of high psychological distress was greater in infected EI zones and States, elevated levels of psychological distress were experienced in horse-owners nationally. Statistical analysis indicated that certain groups were more vulnerable to high psychological distress; specifically younger people, and those with lower levels of formal educational qualifications. Respondents whose principal source of income was from horse-related industry were more than twice as likely to have high psychological distress than those whose primary source of income was not linked to horse-related industry (OR = 2.23; 95% CI: 1.82-2.73; p < 0.001). CONCLUSION: Although, methodologically, this study had good internal validity, it has limited generalisability because it was not possible to identify, bound, or sample the target population accurately. However, this study is the first to collect psychological distress data from an affected population during such a disease outbreak and has potential to inform those involved in assessing the potential psychological impacts of human infectious diseases, such as pandemic influenza.13 page(s

Comparative tissue transcriptomics reveal prompt inter-organ communication in response to local bacterial kidney infection

<p>Abstract</p> <p>Background</p> <p>Mucosal infections elicit inflammatory responses via regulated signaling pathways. Infection outcome depends strongly on early events occurring immediately when bacteria start interacting with cells in the mucosal membrane. Hitherto reported transcription profiles on host-pathogen interactions are strongly biased towards <it>in vitro </it>studies. To detail the local <it>in vivo </it>genetic response to infection, we here profiled host gene expression in a recent experimental model that assures high spatial and temporal control of uropathogenic <it>Escherichia coli </it>(UPEC) infection within the kidney of a live rat.</p> <p>Results</p> <p>Transcriptional profiling of tissue biopsies from UPEC-infected kidney tissue revealed 59 differentially expressed genes 8 h post-infection. Their relevance for the infection process was supported by a Gene Ontology (GO) analysis. Early differential expression at 3 h and 5 h post-infection was of low statistical significance, which correlated to the low degree of infection. Comparative transcriptomics analysis of the 8 h data set and online available studies of early local infection and inflammation defined a core of 80 genes constituting a "General tissue response to early local bacterial infections". Among these, 25% were annotated as interferon-γ (IFN-γ) regulated. Subsequent experimental analyses confirmed a systemic increase of IFN-γ in rats with an ongoing local kidney infection, correlating to splenic, rather than renal <it>Ifng </it>induction and suggested this inter-organ communication to be mediated by interleukin (IL)-23. The use of comparative transcriptomics allowed expansion of the statistical data handling, whereby relevant data could also be extracted from the 5 h data set. Out of the 31 differentially expressed core genes, some represented specific 5 h responses, illustrating the value of comparative transcriptomics when studying the dynamic nature of gene regulation in response to infections.</p> <p>Conclusion</p> <p>Our hypothesis-free approach identified components of infection-associated multi-cellular tissue responses and demonstrated how a comparative analysis allows retrieval of relevant information from lower-quality data sets. The data further define marked representation of IFN-γ responsive genes and a prompt inter-organ communication as a hallmark of an early local tissue response to infection.</p

Genetic Dissection of Strain Dependent Paraquat-induced Neurodegeneration in the Substantia Nigra Pars Compacta

The etiology of the vast majority of Parkinson's disease (PD) cases is unknown. It is generally accepted that there is an interaction between exposures to environmental agents with underlying genetic sensitivity. Recent epidemiological studies have shown that people living in agricultural communities have an increased risk of PD. Within these communities, paraquat (PQ) is one of the most utilized herbicides. PQ acts as a direct redox cycling agent to induce formation of free radicals and when administered to mice induces the cardinal symptoms of parkinsonism, including loss of TH+-positive dopaminergic (DA) neurons in the ventral midbrain's substantia nigra pars compacta (SNpc). Here we show that PQ-induced SNpc neuron loss is highly dependent on genetic background: C57BL/6J mice rapidly lose ∼50% of their SNpc DA neurons, whereas inbred Swiss-Webster (SWR/J) mice do not show any significant loss. We intercrossed these two strains to map quantitative trait loci (QTLs) that underlie PQ-induced SNpc neuron loss. Using genome-wide linkage analysis we detected two significant QTLs. The first is located on chromosome 5 (Chr 5) centered near D5Mit338, whereas the second is on Chr 14 centered near D14Mit206. These two QTLs map to different loci than a previously identified QTL (Mptp1) that controls a significant portion of strain sensitivity to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), suggesting that the mechanism of action of these two parkinsonian neurotoxins are different

Uncovering a Macrophage Transcriptional Program by Integrating Evidence from Motif Scanning and Expression Dynamics

Macrophages are versatile immune cells that can detect a variety of pathogen-associated molecular patterns through their Toll-like receptors (TLRs). In response to microbial challenge, the TLR-stimulated macrophage undergoes an activation program controlled by a dynamically inducible transcriptional regulatory network. Mapping a complex mammalian transcriptional network poses significant challenges and requires the integration of multiple experimental data types. In this work, we inferred a transcriptional network underlying TLR-stimulated murine macrophage activation. Microarray-based expression profiling and transcription factor binding site motif scanning were used to infer a network of associations between transcription factor genes and clusters of co-expressed target genes. The time-lagged correlation was used to analyze temporal expression data in order to identify potential causal influences in the network. A novel statistical test was developed to assess the significance of the time-lagged correlation. Several associations in the resulting inferred network were validated using targeted ChIP-on-chip experiments. The network incorporates known regulators and gives insight into the transcriptional control of macrophage activation. Our analysis identified a novel regulator (TGIF1) that may have a role in macrophage activation

Association of HFE common mutations with Parkinson's disease, Alzheimer's disease and mild cognitive impairment in a Portuguese cohort

Background: Pathological brain iron deposition has been implicated as a source of neurotoxic reactive oxygen species in Alzheimer (AD) and Parkinson diseases (PD). Iron metabolism is associated with the gene hemochromatosis (HFE Human genome nomenclature committee ID: 4886), and mutations in HFE are a cause of the iron mismetabolism disease, hemochromatosis. Several reports have tested the association of HFE variants with neurodegenerative diseases, such as AD and PD with conflicting results.Methods: Genotypes were analysed for the two most common variants of HFE in a series of 130 AD, 55 Mild Cognitive Impairment (MCI) and 132 PD patients. Additionally, a series of 115 healthy age-matched controls was also screened.Results: A statistically significant association was found in the PD group when compared to controls, showing that the presence of the C282Y variant allele may confer higher risk for developing the disease.Conclusion: Taken together these results suggest that the common variants in HFE may be a risk factor for PD, but not for AD in the Portuguese population