Environmental risk factors for autism spectrum disorder (ASD)

Background: Autism Spectrum Disorder (ASD) is a significant public health concern. The prevalence rate of this heterogeneous group of neurological conditions has more than doubled in the US during the last twenty years. The amount and cost of care needed to provide support and services for families impacted by ASD are increasing as well. Current research suggests that the etiology of ASD is not wholly genetic. The objective of this research is to investigate environmental contributors to the disease. Parental, prenatal, and obstetric factors and exposure to air pollutants during the prenatal period were examined for potential associations with ASD status. Methods: Risk factors were extracted from the birth certificates of singleton cases (n=198) and controls (n=4,801) from the Case-Control Study of Personal and Environmental Risk Factors for Childhood Autism in Southwestern Pennsylvania. Cases and controls were born between 2005 and 2009. The 2005 National Air Toxics Assessment (NATA) and the Toxic Release Inventory (TRI) for 2004 – 2009 were used to estimate air pollutant exposure during pregnancy. Logistic regression models estimated the odds of being an ASD case in all investigations. Results: Multivariable logistic regression modelling showed that increased maternal age, greater maternal education, gestational hypertension, cesarean delivery, and maternal infection were independent risk factors for ASD. In the analysis comparing higher quartiles of NATA exposure estimates of metal compounds to the lowest quartile of metal exposure at mother’s residence at the time of her child’s birth, arsenic, chromium, and lead were significantly associated with being an ASD case. However, an analysis of proximity to chromium emitting industrial sites, as reported in the TRI, uncovered no elevated or statistically significant association with ASD status. Conclusions: Maternal and birth characteristics as well as exposure to metal compounds during the prenatal period were shown to have an association with ASD in this case-control study. This research adds to a growing body of literature suggesting that environmental risk factors contribute to the ASD burden. However, improved exposure assessment methods and a prospective study design would aid in establishing a causal association

Regulation of TFIIIB during F9 cell differentiation

<p>Abstract</p> <p>Background</p> <p>Differentiation of F9 embryonal carcinoma (EC) cells into parietal endoderm (PE) provides a tractable model system for studying molecular events during early and inaccessible stages of murine development. PE formation is accompanied by extensive changes in gene expression both in vivo and in culture. One of the most dramatic is the ~10-fold decrease in transcriptional output by RNA polymerase (pol) III. This has been attributed to changes in activity of TFIIIB, a factor that is necessary and sufficient to recruit pol III to promoters. The goal of this study was to identify molecular changes that can account for the low activity of TFIIIB following F9 cell differentiation.</p> <p>Results</p> <p>Three essential subunits of TFIIIB decrease in abundance as F9 cells differentiate; these are Brf1 and Bdp1, which are pol III-specific, and TBP, which is also used by pols I and II. The decreased levels of Brf1 and Bdp1 proteins can be explained by reduced expression of the corresponding mRNAs. However, this is not the case for TBP, which is regulated post-transcriptionally. In proliferating cells, pol III transcription is stimulated by the proto-oncogene product c-Myc and the mitogen-activated protein kinase Erk, both of which bind to TFIIIB. However, c-Myc levels fall during differentiation and Erk becomes inactive through dephosphorylation. The diminished abundance of TFIIIB is therefore likely to be compounded by changes to these positive regulators that are required for its full activity. In addition, PE cells have elevated levels of the retinoblastoma protein RB, which is known to bind and repress TFIIIB.</p> <p>Conclusion</p> <p>The low activity of TFIIIB in PE can be attributed to a combination of changes, any one of which could be sufficient to inhibit pol III transcription. Declining levels of essential TFIIIB subunits and of activators that are required for maximal TFIIIB activity are accompanied by an increase in a potent repressor of TFIIIB. These events provide fail-safe guarantees to ensure that pol III output is appropriate to the diminished metabolic requirements of terminally differentiated cells.</p

The longitudinal development of emotion regulation capacities in children at risk for externalizing disorders

The development of emotional regulation capacities in children at high versus low risk for externalizing disorder was examined in a longitudinal study investigating: a) whether disturbances in emotion regulation precede and predict the emergence of externalizing symptoms; and b) whether sensitive maternal behavior is a significant influence on the development of child emotion regulation. Families experiencing high (n=58) and low (n=63) levels of psychosocial adversity were recruited to the study during pregnancy. Direct observational assessments of child emotion regulation capacities and maternal sensitivity were completed in early infancy, at 12 and 18-months, and at 5-years. Key findings were as follows. First, high risk children showed poorer emotion regulation capacities than their low risk counterparts at every stage of assessment. Second, from 12-months onwards, emotion regulation capacities showed a degree of stability, and were associated with behavioral problems, both concurrently and prospectively. Third, maternal sensitivity was related to child emotion regulation capacities throughout development, with poorer emotion regulation in the high risk group being associated with lower maternal sensitivity. The results are consistent with a causal role for problems in the regulation of negative emotions in the etiology of externalizing psychopathology, and highlight insensitive parenting as a potentially key developmental influence

Protection From Clinical Peripheral Sensory Neuropathy in Alström Syndrome in Contrast to Early-Onset Type 2 Diabetes

OBJECTIVE—Alström syndrome, with type 2 diabetes, and blindness could confer a high risk of foot ulceration. Clinical testing for neuropathy in Alström syndrome and matched young-onset type 2 diabetic subjects was therefore undertaken

The role of CDC48 in the retro-translocation of non-ubiquitinated toxin substrates in plant cells

When the catalytic A subunits of the castor bean toxins ricin and Ricinus communis agglutinin (denoted as RTA and RCA A, respectively) are delivered into the endoplasmic reticulum (ER) of tobacco protoplasts, they become substrates for ER-associated protein degradation (ERAD). As such, these orphan polypeptides are retro-translocated to the cytosol, where a significant proportion of each protein is degraded by proteasomes. Here we begin to characterise the ERAD pathway in plant cells, showing that retro-translocation of these lysine-deficient glycoproteins requires the ATPase activity of cytosolic CDC48. Lysine polyubiquitination is not obligatory for this step. We also show that while RCA A is found in a mannose-untrimmed form prior to its retro-translocation, a significant proportion of newly synthesised RTA cycles via the Golgi and becomes modified by downstream glycosylation enzymes. Despite these differences, both proteins are similarly retro-translocated

2009 Focused Update Incorporated Into the ACC/AHA 2005 Guidelines for the Diagnosis and Management of Heart Failure in Adults A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines Developed in Collaboration With the International Society for Heart and Lung Transplantation

Heart failure (HF) is a major and growing public health problem in the United States. Approximately 5 million patients in this country have HF, and over 550,000 patients are diagnosed with HF for the first time each year. The disorder is the primary reason for 12 to 15 million office visits and 6.5 million hospital days each year. From 1990 to 1999, the annual number of hospitalizations has increased from approximately 810,000 to over 1 million for HF as a primary diagnosis and from 2.4 to 3.6 million for HF as a primary or secondary diagnosis. In 2001, nearly 53 000 patients died of HF as a primary cause. The number of HF deaths has increased steadily despite advances in treatment, in part because of increasing numbers of patients with HF due to better treatment and “salvage” of patients with acute myocardial infarctions (MIs) earlier in life. Heart failure is primarily a condition of the elderly, and thus the widely recognized “aging of the population” also contributes to the increasing incidence of HF. The incidence of HF approaches 10 per 1000 population after age 65, and approximately 80% of patients hospitalized with HF are more than 65 years old. Heart failure is the most common Medicare diagnosis-related group (i.e., hospital discharge diagnosis), and more Medicare dollars are spent for the diagnosis and treatment of HF than for any other diagnosis. The total estimated direct and indirect costs for HF in 2005 were approximately $27.9 billion. In the United States, approximately$2.9 billion annually is spent on drugs for the treatment of HF

Genomic Profiling of Childhood Tumor Patient-Derived Xenograft Models to Enable Rational Clinical Trial Design.

Accelerating cures for children with cancer remains an immediate challenge as a result of extensive oncogenic heterogeneity between and within histologies, distinct molecular mechanisms evolving between diagnosis and relapsed disease, and limited therapeutic options. To systematically prioritize and rationally test novel agents in preclinical murine models, researchers within the Pediatric Preclinical Testing Consortium are continuously developing patient-derived xenografts (PDXs)-many of which are refractory to current standard-of-care treatments-from high-risk childhood cancers. Here, we genomically characterize 261 PDX models from 37 unique pediatric cancers; demonstrate faithful recapitulation of histologies and subtypes; and refine our understanding of relapsed disease. In addition, we use expression signatures to classify tumors for TP53 and NF1 pathway inactivation. We anticipate that these data will serve as a resource for pediatric oncology drug development and will guide rational clinical trial design for children with cancer