Human monoclonal islet specific autoantibodies share features of islet cell and 64 kDa antibodies

The first human monoclonal islet cell antibodies of the IgG class (MICA 1-6) obtained from an individual with Type 1 (insulin-dependent) diabetes mellitus were cytoplasmic islet cell antibodies selected by the indirect immunofluorescence test on pancreas sections. Surprisingly, they all recognized the 64 kDa autoantigen glutamate decarboxylase. In this study we investigated which typical features of cytoplasmic islet cell antibodies are represented by these monoclonals. We show by double immunofluorescence testing that MICA 1-6 stain pancreatic beta cells which is in agreement with the beta-cell specific expression of glutamate decarboxylase. In contrast an islet-reactive IgM monoclonal antibody obtained from a pre-diabetic individual stained all islet cells but lacked the tissue specificity of MICA 1-6 and must therefore be considered as a polyreactive IgM-antibody. We further demonstrate that MICA 1-6 revealed typical features of epitope sensitivity to biochemical treatment of the target tissue which has been demonstrated for islet cell antibodies, and which has been used to argue for a lipid rather than a protein nature of target antigens. Our results provide direct evidence that the epitopes recognized by the MICA are destroyed by methanol/chloroform treatment but reveal a high stability to Pronase digestion compared to proinsulin epitopes. Conformational protein epitopes in glutamate decarboxylase therefore show a sensitivity to biochemical treatment of sections such as ganglioside epitopes. MICA 1-6 share typical features of islet cell and 64 kDa antibodies and reveal that glutamate decarboxylase-reactive islet cell antibodies represent a subgroup of islet cell antibodies present in islet cell antibody-positive sera

Chemical combination effects predict connectivity in biological systems

Efforts to construct therapeutically useful models of biological systems require large and diverse sets of data on functional connections between their components. Here we show that cellular responses to combinations of chemicals reveal how their biological targets are connected. Simulations of pathways with pairs of inhibitors at varying doses predict distinct response surface shapes that are reproduced in a yeast experiment, with further support from a larger screen using human tumour cells. The response morphology yields detailed connectivity constraints between nearby targets, and synergy profiles across many combinations show relatedness between targets in the whole network. Constraints from chemical combinations complement genetic studies, because they probe different cellular components and can be applied to disease models that are not amenable to mutagenesis. Chemical probes also offer increased flexibility, as they can be continuously dosed, temporally controlled, and readily combined. After extending this initial study to cover a wider range of combination effects and pathway topologies, chemical combinations may be used to refine network models or to identify novel targets. This response surface methodology may even apply to non-biological systems where responses to targeted perturbations can be measured

Terrorism in Australia: factors associated with perceived threat and incident-critical behaviours

<p>Abstract</p> <p>Background</p> <p>To help improve incident preparedness this study assessed socio-demographic and socio-economic predictors of perceived risk of terrorism within Australia and willingness to comply with public safety directives during such incidents.</p> <p>Methods</p> <p>The terrorism perception question module was incorporated into the New South Wales Population Health Survey and was completed by a representative sample of 2,081 respondents in early 2007. Responses were weighted against the New South Wales population.</p> <p>Results</p> <p>Multivariate analyses indicated that those with no formal educational qualifications were significantly more likely (OR = 2.10, 95%CI:1.32–3.35, p < 0.001) to think that a terrorist attack is very or extremely likely to occur in Australia and also more likely (OR = 3.62, 95%CI:2.25–5.83, p < 0.001) to be very or extremely concerned that they or a family member would be directly affected, compared to those with a university-level qualification. Speaking a language other than English at home predicted high concern (very/extremely) that self or family would be directly affected (OR = 3.02, 95%CI:2.02–4.53, p < 0.001) and was the strongest predictor of having made associated changes in living (OR = 3.27, 95%CI:2.17–4.93, p < 0.001). Being female predicted willingness to evacuate from public facilities. Speaking a language other than English at home predicted low willingness to evacuate.</p> <p>Conclusion</p> <p>Low education level is a risk factor for high terrorism risk perception and concerns regarding potential impacts. The pattern of concern and response among those of migrant background may reflect secondary social impacts associated with heightened community threat, rather than the direct threat of terrorism itself. These findings highlight the need for terrorism risk communication and related strategies to address the specific concerns of these sub-groups as a critical underpinning of population-level preparedness.</p

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

Costs and Effects of Abdominal versus Laparoscopic Hysterectomy: Systematic Review of Controlled Trials

Objective: Comparative evaluation of costs and effects of laparoscopic hysterectomy (LH) and abdominal hysterectomy (AH). Data sources: Controlled trials from Cochrane Central register of controlled trials, Medline, Embase and prospective trial registers. Selection of studies: Twelve (randomized) controlled studies including the search terms costs, laparoscopy, laparotomy and hysterectomy were identified. Methods: The type of cost analysis, perspective of cost analyses and separate cost components were assessed. The direct and indirect costs were extracted from the original studies. For the cost estimation, hospital stay and procedure costs were selected as most important cost drivers. As main outcome the major complication rate was taken. Findings: Analysis was performed on 2226 patients, of which 1013 (45.5%) in the LH group and 1213 (54.5%) in the AH group. Five studies scored >= 10 points (out of 19) for methodological quality. The reported total direct costs in the LH group ($63,997) were 6.1$60,114). The reported total indirect costs of the LH group ($1,609) were half of the total indirect in the AH group ($3,139). The estimated mean major complication rate in the LH group (14.3%) was lower than in the AH group (15.9%). The estimated total costs in the LH group were $3,884 versus$3,312 in the AH group. The incremental costs for reducing one patient with major complication(s) in the LH group compared to the AH group was $35,750. Conclusions: The shorter hospital stay in the LH group compensates for the increased procedure costs, with less morbidity. LH points in the direction of cost effectiveness, however further research is warranted with a broader costs perspective including long term effects as societal benefit, quality of life and survival

Smoking cessation in severe mental ill health : what works? an updated systematic review and meta-analysis

BACKGROUND: People with severe mental ill health are more likely to smoke than those in the general population. It is therefore important that effective smoking cessation strategies are used to help people with severe mental ill health to stop smoking. This study aims to assess the effectiveness and cost -effectiveness of smoking cessation and reduction strategies in adults with severe mental ill health in both inpatient and outpatient settings. METHODS: This is an update of a previous systematic review. Electronic databases were searched during September 2016 for randomised controlled trials comparing smoking cessation interventions to each other, usual care, or placebo. Data was extracted on biochemically-verified, self-reported smoking cessation (primary outcome), as well as on smoking reduction, body weight, psychiatric symptom, and adverse events (secondary outcomes). RESULTS: We included 26 trials of pharmacological and/or behavioural interventions. Eight trials comparing bupropion to placebo were pooled showing that bupropion improved quit rates significantly in the medium and long term but not the short term (short term RR = 6.42 95% CI 0.82-50.07; medium term RR = 2.93 95% CI 1.61-5.34; long term RR = 3.04 95% CI 1.10-8.42). Five trials comparing varenicline to placebo showed that that the addition of varenicline improved quit rates significantly in the medium term (RR = 4.13 95% CI 1.36-12.53). The results from five trials of specialised smoking cessation programmes were pooled and showed no evidence of benefit in the medium (RR = 1.32 95% CI 0.85-2.06) or long term (RR = 1.33 95% CI 0.85-2.08). There was insufficient data to allowing pooling for all time points for varenicline and trials of specialist smoking cessation programmes. Trials suggest few adverse events although safety data were not always reported. Only one pilot study reported cost effectiveness data. CONCLUSIONS: Bupropion and varenicline, which have been shown to be effective in the general population, also work for people with severe mental ill health and their use in patients with stable psychiatric conditions. Despite good evidence for the effectiveness of smoking cessation interventions for people with severe mental ill health, the percentage of people with severe mental ill health who smoke remains higher than that for the general population

Alert but less alarmed: a pooled analysis of terrorism threat perception in Australia

<p>Abstract</p> <p>Background</p> <p>Previous Australian research has highlighted disparities in community perceptions of the threat posed by terrorism. A study with a large sample size is needed to examine reported concerns and anticipated responses of community sub-groups and to determine their consistency with existing Australian and international findings.</p> <p>Methods</p> <p>Representative samples of New South Wales (NSW) adults completed terrorism perception questions as part of computer assisted telephone interviews (CATI) in 2007 (N = 2081) and 2010 (N = 2038). Responses were weighted against the NSW population. Data sets from the two surveys were pooled and multivariate multilevel analyses conducted to identify health and socio-demographic factors associated with higher perceived risk of terrorism and evacuation response intentions, and to examine changes over time.</p> <p>Results</p> <p>In comparison with 2007, Australians in 2010 were significantly more likely to believe that a terrorist attack would occur in Australia (Adjusted Odd Ratios (AOR) = 1.24, 95%CI:1.06-1.45) but felt less concerned that they would be directly affected by such an incident (AOR = 0.65, 95%CI:0.55-0.75). Higher perceived risk of terrorism and related changes in living were associated with middle age, female gender, lower education and higher reported psychological distress. Australians of migrant background reported significantly lower likelihood of terrorism (AOR = 0.52, 95%CI:0.39-0.70) but significantly higher concern that they would be personally affected by such an incident (AOR = 1.57, 95%CI:1.21-2.04) and having made changes in the way they live due to this threat (AOR = 2.47, 95%CI:1.88-3.25). Willingness to evacuate homes and public places in response to potential incidents increased significantly between 2007 and 2010 (AOR = 1.53, 95%CI:1.33-1.76).</p> <p>Conclusion</p> <p>While an increased proportion of Australians believe that the national threat of terrorism remains high, concern about being personally affected has moderated and may reflect habituation to this threat. Key sub-groups remain disproportionately concerned, notably those with lower education and migrant groups. The dissonance observed in findings relating to Australians of migrant background appears to reflect wider socio-cultural concerns associated with this issue. Disparities in community concerns regarding terrorism-related threat require active policy consideration and specific initiatives to reduce the vulnerabilities of known risk groups, particularly in the aftermath of future incidents.</p

Clustered Gene Expression Changes Flank Targeted Gene Loci in Knockout Mice

Gene expression profiling using microarrays is a powerful technology widely used to study regulatory networks. Profiling of mRNA levels in mutant organisms has the potential to identify genes regulated by the mutated protein.Using tissues from multiple lines of knockout mice we have examined genome-wide changes in gene expression. We report that a significant proportion of changed genes were found near the targeted gene.The apparent clustering of these genes was explained by the presence of flanking DNA from the parental ES cell. We provide recommendations for the analysis and reporting of microarray data from knockout mice