Visual and auditory emotion recognition problems as familial cross-disorder phenomenon in ASD and ADHD

Autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) are frequently comorbid disorders. Emotion recognition problems are considered an important familial deficit in ASD, but this is unknown in ADHD. Very few studies have directly compared emotion recognition performance of youth with ASD and/or ADHD and of their unaffected siblings across age to quantify the contribution of emotion recognition problems to the ADHD phenotype. We therefore devised a study of 64 ASD+ADHD participants, 89 ASD-only participants, 111 ADHD-only participants, 122 unaffected ASD(+ADHD) siblings, 69 unaffected ADHD-only siblings and 220 controls aged 7–18 years, who had completed two tasks assessing auditory and visual emotion recognition. Factor analysis was used to detect underlying dimensions of emotion recognition capacity. Linear mixed models were used to compare performance across groups and to assess age effects. The factor-analysis revealed four factors separating speed and accuracy regarding visual and auditory emotion recognition. ASD+ADHD, ASD-only, and ADHD-only participants all performed worse than controls. ASD+ADHD, ASD-only, and ADHD-only participants did not differ in the severity of their emotion recognition problems. Both unaffected sibling groups performed intermediate between patients and controls. For ASD+ADHD and ADHD-only participants, group differences were more marked in adolescence than childhood, whereas in ASD participants this was not observed. We conclude that emotion recognition problems are a familial deficit in ADHD to a similar extent as in ASD. Emotion recognition problems specifically - and social cognition problems more generally - should be assessed in clinical practice for ADHD.     

Enhanced selective cellular uptake and cytotoxicity of epidermal growth factor-conjugated liposomes containing curcumin on EGFR-overexpressed pancreatic cancer cells

Pancreatic cancer is one of the most malignant cancers with a high mortality rate. Some types of pancreatic cancer cells overexpress epidermal growth factor receptor (EGFR), which is a potential target for anticancer agents. In this study, we examined the effect of epidermal growth factor (EGF)-conjugated liposomes containing curcumin (EGF-LP-Cur) on three different EGFR-expressed human pancreatic cancer cell lines, BxPC-3, Panc-1 and Mia Paca-2. We have demonstrated that it is feasible to prepare liposomal vesicles of EGF-LP-Cur and that it is stable in the liquid vehicle at ambient conditions for three weeks. In addition, the formulation of curcumin had higher cytotoxicity on BxPC-3 than on any other cells. It is also shown that the cellular uptake of curcumin on BxPC-3, which is essential for the cytotoxicity, is associated with EGFR-mediated mechanism of action. In summary, our results have showed that targeting EGFR with EGF-conjugated curcumin liposomes enhanced the antitumor activity of curcumin against human pancreatic cancer cells.     

Examining the Association Between Maternal Smoking During Pregnancy and Child Behavior Problems Using Quality-Adjusted Life Years

Objectives Examining the association between maternal smoking and losses in childhood health-related quality of life due to behavior problems provides parents and policymakers another tool for the valuation of smoking cessation during pregnancy. Methods Using the National Longitudinal Survey of Youth 1979 Child and Young Adult data, this study retrospectively examined a cohort of 4114 women and 8668 children. In addition to questions focusing on maternal smoking and general demographics, each survey included the Behavior Problems Index (BPI), a 28-item questionnaire with six subscales measuring childhood behavior problems (antisocial behavior, anxiousness/depression, headstrongness, hyperactivity, immature dependency, and peer conflict/social withdrawal). Responses to the BPI, completed by mothers with children ages 4–14, were summarized on a QALY scale using published preference weights. Results Children whose mothers smoked during pregnancy experience additional QALY losses of 0.181, on average, per year due to increased behavior problems. Boys suffered larger QALY losses associated with maternal smoking (0.242) compared to girls (0.119; p value?=?.021), regardless of age. Moreover, heavier smoking during pregnancy (i.e., 1 or more packs/day) was associated with larger QALY losses (0.282; p-value?<?.001). Conclusions for Practice These findings illustrate the burden of maternal smoking during pregnancy on child health, namely behavioral problems. The losses in QALYs may be incorporated into economic evaluations for smoking cessation interventions during pregnancy. Future research will investigate how maternal smoking following childbirth is associated with child QALYs.     

Precision medicine in chronic disease management: The multiple sclerosis BioScreen

We present a precision medicine application developed for multiple sclerosis (MS): the MS BioScreen. This new tool addresses the challenges of dynamic management of a complex chronic disease; the interaction of clinicians and patients with such a tool illustrates the extent to which translational digital medicine—that is, the application of information technology to medicine—has the potential to radically transform medical practice. We introduce 3 key evolutionary phases in displaying data to health care providers, patients, and researchers: visualization (accessing data), contextualization (understanding the data), and actionable interpretation (real‐time use of the data to assist decision making). Together, these form the stepping stones that are expected to accelerate standardization of data across platforms, promote evidence‐based medicine, support shared decision making, and ultimately lead to improved outcomes. Ann Neurol 2014;76:633–642     

The Target for Statins,HMG-CoA Reductase,Is Expressed in Ductal Carcinoma-In Situ and May Predict Patient Response to Radiotherapy

Background

Patients with ductal carcinoma-in-situ (DCIS) are currently not prescribed adjuvant systemic treatment after surgery and radiotherapy. Prediction of DCIS patients who would benefit from radiotherapy is warranted. Statins have been suggested to exert radio-sensitizing effects. The target for cholesterol-lowering statins is HMG-CoA reductase (HMGCR), the rate-limiting enzyme in the mevalonate pathway. The aim of this study was to examine HMGCR expression in DCIS and study its treatment predictive value.

Methods

A population-based cohort including 458 women diagnosed with primary DCIS between 1986 and 2004 were followed until November 2011 to study long-term survival. Tumor tissue microarrays were constructed, and immunohistochemical analyses were performed to detect cytoplasmic protein expression of HMGCR. The association between DCIS HMGCR expression and invasive breast cancer recurrence-free survival (RFS_inv) and overall survival (OS) was analyzed by Kaplan–Meier curves, log rank test, and Cox proportional hazard analysis.

Results

HMGCR was strongly expressed in 24 % of the assessed DCIS samples, moderately expressed in 46 %, and weakly expressed in 23 %; no expression was detected in 7 % of the samples. During the follow-up time (median 13.8 years), 61 patients were diagnosed with an invasive breast cancer recurrence, and 80 patients died. A crude analysis showed no survival benefit from radiotherapy. However, patients with strong HMGCR expression showed an improved RFS_inv (log rank, p = 0.03) and OS (log rank, p = 0.04) after radiotherapy. No statistically significant interaction was observed for HMGCR and radiotherapy (RFS_inv p = 0.69 and OS p = 0.29).

Conclusions

This study demonstrates HMGCR expression in DCIS and suggests HMGCR as a predictive marker of response to postoperative radiotherapy in DCIS, although the test for interaction was nonsignificant. Future DCIS studies addressing the potential of statin treatment targeting HMGCR are warranted.     

Stabilization of HAC1 Influenza Vaccine by Spray Drying: Formulation Development and Process Scale-Up

Purpose

Stable vaccines with long shelf lives and reduced dependency on the cold chain are ideal for stockpiling and rapid deployment during public emergencies, including pandemics. Spray drying is a low-cost process that has potential to produce vaccines stable at a wide range of temperatures. Our aim was to develop a stable formulation of a recombinant H1N1 influenza hemagglutinin vaccine candidate and take it to pilot-scale spray-drying production.

Methods

Eight formulations containing different excipients were produced and assayed for antigen stability, powder characteristics, and immunogenicity after storage at a range of temperatures, resulting in the identification of four promising candidates. A pilot-scale spray-drying process was then developed for further testing of one formulation.

Results

The pilot-scale process was used to reproducibly manufacture three batches of the selected formulation with yields >90%. All batches had stable physical properties and in vitro potency for 6 months at temperatures from ?20°C to +50°C. Formulations stored for 3 months elicited immunogenic responses in mice equivalent to a frozen lot of bulk vaccine used as a stability control.

Conclusions

This study demonstrates the feasibility of stabilizing subunit vaccines using a spray-drying process and the suitability of the process for manufacturing a candidate product.

     

Heparin-induced thrombocytopenia/thrombosis in a transgenic mouse model requires human platelet factor 4 and platelet activation through FcgammaRIIA

Heparin-induced thrombocytopenia/thrombosis (HIT/HITT) is a severe, life-threatening complication that occurs in 1% to 3% of patients exposed to heparin. Interactions between heparin, human platelet factor 4 (hPF4), antibodies to the hPF4/heparin complex, and the platelet Fc receptor (FcR) for immunoglobulin G, FcgammaRIIA, are the proposed primary determinants of the disease on the basis of in vitro studies. The goal of this study was to create a mouse model that recapitulates the disease process in humans in order to understand the factors that predispose some patients to develop thrombocytopenia and thrombosis and to investigate new therapeutic approaches. Mice that express both human platelet FcgammaRIIA and hPF4 were generated. The FcgammaRIIA/hPF4 mice and controls, transgenic for either FcgammaRIIA or hPF4, were injected with KKO, a mouse monoclonal antibody specific for hPF4/heparin complexes, and then received heparin (20 U/d). Nadir platelet counts for KKO/heparin-treated FcgammaRIIA/hPF4 mice were 80% below baseline values, significantly different (P <.001) from similarly treated controls. FcgammaRIIA/hPF4 mice injected with KKO and 50 U/d heparin developed shock and showed fibrin-rich thrombi in multiple organs, including thrombosis in the pulmonary vasculature. This is the first mouse model of HIT to recapitulate the salient features of the human disease and demonstrates that FcgammaRIIA and hPF4 are both necessary and sufficient to replicate HIT/HITT in an animal model. This model should facilitate the identification of factors that modulate disease expression and the testing of novel therapeutic interventions.     

Familial idiopathic pulmonary fibrosis: clinical features and outcome

STUDY OBJECTIVES: Familial idiopathic pulmonary fibrosis (FIPF) has been defined as idiopathic pulmonary fibrosis (IPF) occurring in two or more members of a family. The clinical course of FIPF has not been fully defined. Accordingly, the current study was undertaken to establish clinical, radiologic, and histologic features, and survival in a consecutive series of patients with FIPF. DESIGN: Retrospective analysis of clinical, radiologic, and pathologic data from a consecutive series of patients with FIPF who were seen at Mayo Medical Center. Survival in patients with FIPF was contrasted to that of previously characterized patients with nonfamilial IPF who were evaluated at our institution. SETTING: Tertiary referral medical center. PATIENTS: We screened 47 patients and family members with FIPF from 15 families who were identified between the years 1992 and 2002. We further analyzed the subgroup of FIPF patients that was composed of 27 patients from 15 families in whom the complete clinical course was monitored at our institution. MEASUREMENTS: All patients exhibited clinical features that were compatible with IPF and either compatible high-resolution CT (HRCT) scan findings or histologic evidence of usual interstitial pneumonia. Clinical data, including symptoms, physical findings, HRCT scan findings, lung function test results, biopsy results, and survival were abstracted from the clinical records. RESULTS: Compared to patients with nonfamilial IPF, patients with FIPF did not demonstrate any notable differences in clinical, radiologic, or pathologic features. We observed that the total number of affected members in a family with FIPF was a significant risk factor for earlier mortality (p = 0.0157; hazard ratio, 1.434). Overall, however, patients with FIPF had a statistically similar outcome to those patients with nonfamilial IPF. CONCLUSIONS: Although uncommon, FIPF represents a distinct syndrome, which has clinical features and patient survival rates that are similar to those of nonfamilial IPF.