Rubella virus infection, the Congenital Rubella Syndrome, and the link to autism

Rubella is a systemic virus infection that is usually mild. It can, however, cause severe birth defects known as the congenital rubella syndrome (CRS) when infection occurs early in pregnancy. As many as 8%–13% of children with CRS developed autism during the rubella epidemic of the 1960s compared to the background rate of about 1 new case per 5000 children. Rubella infection and CRS are now rare in the U.S. and in Europe due to widespread vaccination. However, autism rates have risen dramatically in recent decades to about 3% of children today, with many cases appearing after a period of normal development (‘regressive autism’). Evidence is reviewed here suggesting that the signs and symptoms of rubella may be due to alterations in the hepatic metabolism of vitamin A (retinoids), precipitated by the acute phase of the infection. The infection causes mild liver dysfunction and the spillage of stored vitamin A compounds into the circulation, resulting in an endogenous form of hypervitaminosis A. Given that vitamin A is a known teratogen, it is suggested that rubella infection occurring in the early weeks of pregnancy causes CRS through maternal liver dysfunction and exposure of the developing fetus to excessive vitamin A. On this view, the multiple manifestations of CRS and associated autism represent endogenous forms of hypervitaminosis A. It is further proposed that regressive autism results primarily from post-natal influences of a liver-damaging nature and exposure to excess vitamin A, inducing CRS-like features as a function of vitamin A toxicity, but without the associated dysmorphogenesis. A number of environmental factors are discussed that may plausibly be candidates for this role, and suggestions are offered for testing the model. The model also suggests a number of measures that may be effective both in reducing the risk of fetal CRS in women who acquire rubella in their first trimester and in reversing or minimizing regressive autism among children in whom the diagnosis is suspected or confirmed

A Plan to Facilitate the Early Career Development of Minority Scholars in the Health Sciences

http://dx.doi.org/10.1080/1937191100374817

BronchUK:protocol for an observational cohort study and biobank in bronchiectasis

Bronchiectasis has been a largely overlooked disease area in respiratory medicine. This is reflected by a shortage of large-scale studies and lack of approved therapies, in turn leading to a variation of treatment across centres. BronchUK (Bronchiectasis Observational Cohort and Biobank UK) is a multicentre, prospective, observational cohort study working collaboratively with the European Multicentre Bronchiectasis Audit and Research Collaboration project. The inclusion criteria for patients entering the study are a clinical history consistent with bronchiectasis and computed tomography demonstrating bronchiectasis. Main exclusion criteria are 1) patients unable to provide informed consent, 2) bronchiectasis due to known cystic fibrosis or where bronchiectasis is not the main or co-dominant respiratory disease, 3) age <18 years, and 4) prior lung transplantation for bronchiectasis. The study is aligned to standard UK National Health Service (NHS) practice with an aim to recruit a minimum of 1500 patients from across at least nine secondary care centres. Patient data collected at baseline includes demographics, aetiology testing, comorbidities, lung function, radiology, treatments, microbiology and quality of life. Patients are followed up annually for a maximum of 5 years and, where able, blood and/or sputa samples are collected and stored in a central biobank. BronchUK aims to collect robust longitudinal data that can be used for analysis into current NHS practice and patient outcomes, and to become an integral resource to better inform future interventional studies in bronchiectasis

Targeting DNA Damage Response and Replication Stress in Pancreatic Cancer

Background and aims: Continuing recalcitrance to therapy cements pancreatic cancer (PC) as the most lethal malignancy, which is set to become the second leading cause of cancer death in our society. The study aim was to investigate the association between DNA damage response (DDR), replication stress and novel therapeutic response in PC to develop a biomarker driven therapeutic strategy targeting DDR and replication stress in PC. Methods: We interrogated the transcriptome, genome, proteome and functional characteristics of 61 novel PC patient-derived cell lines to define novel therapeutic strategies targeting DDR and replication stress. Validation was done in patient derived xenografts and human PC organoids. Results: Patient-derived cell lines faithfully recapitulate the epithelial component of pancreatic tumors including previously described molecular subtypes. Biomarkers of DDR deficiency, including a novel signature of homologous recombination deficiency, co-segregates with response to platinum (P &lt; 0.001) and PARP inhibitor therapy (P &lt; 0.001) in vitro and in vivo. We generated a novel signature of replication stress with which predicts response to ATR (P &lt; 0.018) and WEE1 inhibitor (P &lt; 0.029) treatment in both cell lines and human PC organoids. Replication stress was enriched in the squamous subtype of PC (P &lt; 0.001) but not associated with DDR deficiency. Conclusions: Replication stress and DDR deficiency are independent of each other, creating opportunities for therapy in DDR proficient PC, and post-platinum therapy

Understanding Mass Panic and Other Collective Responses to Threat and Disaster

While mass panic (and/or violence) and self-preservation are often assumed to be the natural response to physical danger and perceived entrapment, the literature indicates that expressions of mutual aid are common and often predominate, and collective flight may be so delayed that survival is threatened. In fact, the typical response to a variety of threats and disasters is not to flee but to seek the proximity of familiar persons and places; moreover, separation from attachment figures is a greater stressor than physical danger. Such observations can be explained by an alternative &quot;social attachment&quot; model that recognizes the fundamentally gregarious nature of human beings and the primacy of attachments. In the relatively rare instances where flight occurs, the latter can be understood as one aspect of a more general affiliative response that involves escaping from certain situations and moving toward other situations that are perceived as familiar but which may not necessarily be objectively safe. The occurrence of flight-and-affiliation depends mainly on the social context and especially the whereabouts of familiar persons (i.e., attachment figures); their physical presence has a calming effect and reduces the probability of flight-and-affiliation, while their absence has the opposite effect. Combining the factors of perceived physical danger and the location of attachment figures results in a four-fold typology that encompasses a wide spectrum of collective responses to threat and disaster. Implications of the model for predicting community responses to terrorist attacks and/or use of weapons of mass destruction are briefly discussed

Understanding health disparities affecting people of West Central African descent in the United States: An evolutionary perspective

Abstract Human populations adapting to diverse aspects of their environment such as climate and pathogens leave signatures of genetic variation. This principle may apply to people of West Central African descent in the United States, who are at increased risk of certain chronic conditions and diseases compared to their European counterparts. Less well known is that they are also at reduced risk of other diseases. While discriminatory practices in the United States continue to affect access to and the quality of healthcare, the health disparities affecting African Americans may also be due in part to evolutionary adaptations to the original environment of sub‐Saharan Africa, which involved continuous exposure to the vectors of potentially lethal endemic tropical diseases. Evidence is presented that these organisms selectively absorb vitamin A from the host, and its use in parasite reproduction contributes to the signs and symptoms of the respective diseases. These evolutionary adaptations included (1) sequestering vitamin A away from the liver to other organs, to reduce accessibility to the invaders; and (2) reducing the metabolism and catabolism of vitamin A (vA), causing it to accumulate to subtoxic concentrations and weaken the organisms, thereby reducing the risk of severe disease. However, in the environment of North America, lacking vA‐absorbing parasites and with a mainly dairy‐based diet that is high in vA, this combination of factors is hypothesized to lead to the accumulation of vA and to increased sensitivity to vA as a toxin, which contribute to the health disparities affecting African Americans. vA toxicity is linked to numerous acute and chronic conditions via mitochondrial dysfunction and apoptosis. Subject to testing, the hypothesis suggests that the adoption of traditional or modified West Central African‐style diets that are low in vA and high in vA‐absorbing fiber hold promise for disease prevention and treatment, and as a population‐based strategy for health maintenance and longevity

Toward an Effective Long-Term Strategy for Preventing Motor Vehicle Crashes and Injuries

Casualties due to motor vehicle crashes (MVCs) include some 40,000 deaths each year in the United States and one million deaths worldwide. One strategy that has been recommended for improving automobile safety is to lower speed limits and enforce them with speed cameras. However, motor vehicles can be hazardous even at low speeds whereas properly protected human beings can survive high-speed crashes without injury. Emphasis on changing driver behavior as the focus for road safety improvements has been largely unsuccessful; moreover, drivers today are increasingly distracted by secondary tasks such as cell phone use and texting. Indeed, the true limiting factor in vehicular safety is the capacity of human beings to sense and process information and to make rapid decisions. Given that dramatic reductions in injuries and deaths from MVCs have occurred over the past century due to improvements in safety technology, despite increases in the number of vehicles on the road and miles driven per vehicle, we propose that an effective long-term strategy for reducing MVC-related injury would be continued technological innovation in vehicle design, aimed at progressively removing the driver from routine operational decision-making. Once this is achieved, high rates of speed could be achieved on open highways, with minimal risk of crashes and injury to occupants and pedestrians