Antibodies against heart muscle and nuclear constituents in cardiomyopathy,

The prevalence of HAB and ANA was determined in eight patients with idiopathic hypertrophic subaortic stenosis (IHSS) and 35 patients with cardiomyopathy (CM). HAB was found in 88 per cent of patients with IHSS and in 17 per cent of those with CM. Antinuclear antibody was found in 63 per cent of patients with IHSS and 43 per cent of those with CM. Aging alone was not responsible for the high prevalence of ANA in the former group, but may be partly so in the latter. There was an increased tendency for women in both groups to have ANA. An increased serum concentration of IgM was also observed in women in the IHSS and CM groups. Serum concentrations of IgG and IgA, precipitating antibodies to nuclear constituents, rheumatoid factors, and a positive serologic test for syphilis were not increased in patients with idiopathic cardiomyopathy. Positivity to HAB and ANA did not remain constant and was not present frequently in sera in follow-up studies of these patients. No instance of a negative test becoming positive was recorded for either HAB or ANA. The high prevalence of ANA in patients with IHSS and CM and an increased prevalence of HAB in patients with IHSS may suggest that an autoimmune disturbance is operative in these forms of cardiomyopathy.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/34168/1/0000456.pd

Pathogenic implications of age of onset in juvenile rheumatoid arthritis

An analysis of age of onset in juvenile rheumatoid arthritis was performed in the last 300 children seen in our clinic. There was a peak age of onset in girls at 1 to 3 years. Distribution of age of onset in boys was bimodal with the first peak at 2 years of age and the second at 9 years. There was no accentuation of frequency in either sex in the 10- to 14-year age group. The distribution of age of onset was bimodal in both monarticular and polyarticular onset of disease, but no particular modal age of onset was seen with systemic onset of disease. It is possible that these data reflect that JRA is not a homogeneous disease, or that there are age-sex related differences in host susceptibility or pathogenoc agents.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/37725/1/1780180309_ftp.pd

A functional-cognitive framework for attitude research

In attitude research, behaviours are often used as proxies for attitudes and attitudinal processes. This practice is problematic because it conflates the behaviours that need to be explained (explanandum) with the mental constructs that are used to explain these behaviours (explanans). In the current chapter we propose a meta-theoretical framework that resolves this problem by distinguishing between two levels of analysis. According to the proposed framework, attitude research can be conceptualised as the scientific study of evaluation. Evaluation is defined not in terms of mental constructs but in terms of elements in the environment, more specifically, as the effect of stimuli on evaluative responses. From this perspective, attitude research provides answers to two questions: (1) Which elements in the environment moderate evaluation? (2) What mental processes and representations mediate evaluation? Research on the first question provides explanations of evaluative responses in terms of elements in the environment (functional level of analysis); research on the second question offers explanations of evaluation in terms of mental processes and representations (cognitive level of analysis). These two levels of analysis are mutually supportive, in that better explanations at one level lead to better explanations at the other level. However, their mutually supportive relation requires a clear distinction between the concepts of their explanans and explanandum, which are conflated if behaviours are treated as proxies for mental constructs. The value of this functional-cognitive framework is illustrated by applying it to four central questions of attitude research

Influence of Nanoparticle Size and Shape on Oligomer Formation of an Amyloidogenic Peptide

Understanding the influence of macromolecular crowding and nanoparticles on the formation of in-register $\beta$-sheets, the primary structural component of amyloid fibrils, is a first step towards describing \emph{in vivo} protein aggregation and interactions between synthetic materials and proteins. Using all atom molecular simulations in implicit solvent we illustrate the effects of nanoparticle size, shape, and volume fraction on oligomer formation of an amyloidogenic peptide from the transthyretin protein. Surprisingly, we find that inert spherical crowding particles destabilize in-register $\beta$-sheets formed by dimers while stabilizing $\beta$-sheets comprised of trimers and tetramers. As the radius of the nanoparticle increases crowding effects decrease, implying smaller crowding particles have the largest influence on the earliest amyloid species. We explain these results using a theory based on the depletion effect. Finally, we show that spherocylindrical crowders destabilize the ordered $\beta$-sheet dimer to a greater extent than spherical crowders, which underscores the influence of nanoparticle shape on protein aggregation

Accessible Content and Accessibility Experiences: The Interplay of Declarative and Experiential Information in Judgment

Recall tasks render 2 distinct sources of information available: the recalled content and the experienced ease or difficulty with which it can be brought to mind. Because retrieving many pieces of information is more difficult than retrieving only a few, reliance on accessible content and subjective accessibility experiences leads to opposite judgmental outcomes. People are likely to base judgments on accessibility experiences when they adopt a heuristic processing strategy and the informational value of the experience is not called into question. When the experience is considered nondiagnostic, or when a systematic processing strategy is adopted, people rely on accessible content. Implications for the operation of the availability heuristic and the emergence of knowledge accessibility effects are discussed.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/68686/2/10.1207_s15327957pspr0202_2.pd

The risk and nature of flares in juvenile idiopathic arthritis: Results from the ReACCh-Out cohort

Objective To describe probabilities and characteristics of disease flares in children with juvenile idiopathic arthritis ( JIA) and to identify clinical features associated with an increased risk of flare. Methods We studied children in the Research in Arthritis in Canadian Children emphasizing Outcomes (ReACCh-Out) prospective inception cohort. A flare was defined as a recurrence of disease manifestations after attaining inactive disease and was called significant if it required intensification of treatment. Probability of first flare was calculated with Kaplan-Meier methods, and associated features were identified using Cox regression. Results 1146 children were followed up a median of 24 months after attaining inactive disease. We observed 627 first flares (54.7% of patients) with median active joint count of 1, physician global assessment (PGA) of 12 mm and duration of 27 weeks. Within a year after attaining inactive disease, the probability of flare was 42.5% (95% CI 39% to 46%) for any flare and 26.6% (24% to 30%) for a significant flare. Within a year after stopping treatment, it was 31.7% (28% to 36%) and 25.0% (21% to 29%), respectively. A maximum PGA \u3e30 mm, maximum active joint count \u3e4, rheumatoid factor (RF)-positive polyarthritis, antinuclear antibodies (ANA) and receiving disease-modifying antirheumatic drugs (DMARDs) or biological agents before attaining inactive disease were associated with increased risk of flare. Systemic JIA was associated with the lowest risk of flare. Conclusions In this real-practice JIA cohort, flares were frequent, usually involved a few swollen joints for an average of 6 months and 60% led to treatment intensification. Children with a severe disease course had an increased risk of flare

Predicting which children with juvenile idiopathic arthritis will not attain early remission with conventional treatment: Results from the Reacch-out cohort

Objective. To estimate the probability of early remission with conventional treatment for each child with juvenile idiopathic arthritis (JIA). Children with a low chance of remission may be candidates for initial treatment with biologics or triple disease-modifying antirheumatic drugs (DMARD). Methods. We used data from 1074 subjects in the Research in Arthritis in Canadian Children emphasizing Outcomes (ReACCh-Out) cohort. The predicted outcome was clinically inactive disease for ≥ 6 months starting within 1 year of JIA diagnosis in patients who did not receive early biologic agents or triple DMARD. Models were developed in 200 random splits of 75% of the cohort and tested on the remaining 25% of subjects, calculating expected and observed frequencies of remission and c-index values. Results. Our best Cox logistic model combining 18 clinical variables a median of 2 days after diagnosis had a c-index of 0.69 (95% CI 0.67-0.71), better than using JIA category alone (0.59, 95% CI 0.56-0.63). Children in the lowest probability decile had a 20% chance of remission and 21% attained remission; children in the highest decile had a 69% chance of remission and 73% attained remission. Compared to 5% of subjects identified by JIA category alone, the model identified 14% of subjects as low chance of remission (probability \u3c 0.25), of whom 77% failed to attain remission. Conclusion. Although the model did not meet our a priori performance threshold (c-index \u3e 0.70), it identified 3 times more subjects with low chance of remission than did JIA category alone, and it may serve as a benchmark for assessing value added by future laboratory/imaging biomarkers

Optimized EGFR blockade strategies in <i>EGFR</i> addicted gastroesophageal adenocarcinomas

Purpose: Gastric and gastroesophageal adenocarcinomas represent the third leading cause of cancer mortality worldwide. Despite significant therapeutic improvement, the outcome of patients with advanced gastroesophageal adenocarcinoma is poor. Randomized clinical trials failed to show a significant survival benefit in molecularly unselected patients with advanced gastroesophageal adenocarcinoma treated with anti-EGFR agents.Experimental Design: We performed analyses on four cohorts: IRCC (570 patients), Foundation Medicine, Inc. (9,397 patients), COG (214 patients), and the Fondazione IRCCS Istituto Nazionale dei Tumori (206 patients). Preclinical trials were conducted in patient-derived xenografts (PDX).Results: The analysis of different gastroesophageal adenocarcinoma patient cohorts suggests that EGFR amplification drives aggressive behavior and poor prognosis. We also observed that EGFR inhibitors are active in patients with EGFR copy-number gain and that coamplification of other receptor tyrosine kinases or KRAS is associated with worse response. Preclinical trials performed on EGFR-amplified gastroesophageal adenocarcinoma PDX models revealed that the combination of an EGFR mAb and an EGFR tyrosine kinase inhibitor (TKI) was more effective than each monotherapy and resulted in a deeper and durable response. In a highly EGFR-amplified nonresponding PDX, where resistance to EGFR drugs was due to inactivation of the TSC2 tumor suppressor, cotreatment with the mTOR inhibitor everolimus restored sensitivity to EGFR inhibition.Conclusions: This study underscores EGFR as a potential therapeutic target in gastric cancer and identifies the combination of an EGFR TKI and a mAb as an effective therapeutic approach. Finally, it recognizes mTOR pathway activation as a novel mechanism of primary resistance that can be overcome by the combination of EGFR and mTOR inhibitors

Protocol for a randomised controlled trial investigating self-help email messages for sub-threshold depression: the Mood Memos study

<p>Abstract</p> <p>Background</p> <p>Sub-threshold depression is common, impairs functioning, and increases the risk of developing major depression. Although psychological treatments have been investigated for sub-threshold depression, they are costly. A less costly alternative could be an educational health promotion campaign about effective self-help for depression symptoms. The aim of the study is to test the efficacy of a low-cost email-based mental health promotion campaign in changing self-help behaviour and preventing more severe depression in adults with sub-threshold depression.</p> <p>Methods/Design</p> <p>The project is a randomised controlled trial of an automated preventive email-intervention aimed at people with sub-threshold depression. Adults aged 18+ with sub-threshold depression (as measured with the Patient Health Questionnaire-9), who are not already receiving professional treatment for depression, are eligible for admission to the study. Internet users will sign up via the study website <url>http://www.moodmemos.com</url> and be randomly allocated to receive emails twice weekly for six weeks containing either self-help coping advice or general information about depression as a control. Outcomes will be assessed at the start, midpoint, and end of the intervention, as well as six months later. Outcomes assessed include symptoms, incidence of major depression, psychological distress, social and occupational functioning, coping strategies, and coping self-efficacy. The primary hypothesis is that the Mood Memo emails containing coping strategies will reduce depression symptoms and be better at preventing major depression than the control emails that contain general information about depression.</p> <p>Discussion</p> <p>Promotion of actions an individual can take to prevent physical disease is a technique often used in public health. This study applies this approach to mental health, and explores whether a low-cost, easily disseminated email-based campaign can improve self-help coping behaviour and prevent depression in adults with sub-threshold depression.</p> <p>Trial Registration</p> <p>Australia and New Zealand Clinical Trials Register (ANZCTR): <a href="http://www.anzctr.org.au/ACTRN12609000925246.aspx">ACTRN12609000925246</a></p