Do we need neuroimaging in every case of near-hanging?: experience from a level 1 trauma center and analysis of the National Trauma Data Bank.

PURPOSE: Our study analyzes imaging results in near-hanging to determine what neuroimaging workup is necessary. We evaluate GCS as a clinical predictor to help guide imaging choice. METHODS: This is a retrospective study of patients from a level one trauma center and from the National Trauma Data Bank (NTDB). We classified injuries into categories based on the likelihood that CT played an important role in their diagnosis and management. We assessed whether a normal Glasgow Coma Scale (GCS) could exclude clinically important injuries. Chi square was used to test for significance for categorical variables. Multivariate logistic regression was used for multivariate analysis. RESULTS: CT showed structural brain findings in 0% of patients from our facility (local patients) and 11.7% of NTDB patients. Of local patients and NTDB patients, 1.4% and 6.6% had blunt cerebral vascular injury (BCVI) respectively. Of local patients and NTDB patients, 1.4% and 3.3% had a cervical spine fracture or dislocation, respectively. Mortality for patients with GCS 15 versus GCS < 15 was 0 versus 26.9% for local patients (p = 0.004) and 0 versus 43.8% for NTDB (p < 0.001). Structural brain injury for patients with GCS 15 versus GCS < 15 for isolated hanging was 0 versus 14.9% for NTDB (p < 0.001). GCS 15 was an independent predictor of survival and freedom from brain injury (p < 0.001), but not neck injury. CONCLUSION: GCS 15 is a significant independent predictor of survival and freedom from brain injury in near-hanging. GCS 15 rules out intracranial injury likely to require intervention with negative predictive value of 100%. GCS of 15 does not rule out critical neck injury.

HGFAC is a ChREBP-regulated hepatokine that enhances glucose and lipid homeostasis.

Carbohydrate response element-binding protein (ChREBP) is a carbohydrate-sensing transcription factor that regulates both adaptive and maladaptive genomic responses in coordination of systemic fuel homeostasis. Genetic variants in the ChREBP locus associate with diverse metabolic traits in humans, including circulating lipids. To identify novel ChREBP-regulated hepatokines that contribute to its systemic metabolic effects, we integrated ChREBP ChIP-Seq analysis in mouse liver with human genetic and genomic data for lipid traits and identified hepatocyte growth factor activator (HGFAC) as a promising ChREBP-regulated candidate in mice and humans. HGFAC is a protease that activates the pleiotropic hormone hepatocyte growth factor. We demonstrate that HGFAC-KO mice had phenotypes concordant with putative loss-of-function variants in human HGFAC. Moreover, in gain- and loss-of-function genetic mouse models, we demonstrate that HGFAC enhanced lipid and glucose homeostasis, which may be mediated in part through actions to activate hepatic PPARγ activity. Together, our studies show that ChREBP mediated an adaptive response to overnutrition via activation of HGFAC in the liver to preserve glucose and lipid homeostasis.

Intestinal worms eating neuropsychiatric disorders? Apparently so.

A number of factors in Western society, including inflammatory diets, sedentary lifestyles, vitamin D deficiency and chronic psychological stress, are known to induce inflammation and to be associated with neuropsychiatric disorders. One factor that is emerging as a potential inflammation inducing factor is biota depletion, or loss of biodiversity from the ecosystem of the human body as a result of industrialization. Originally known as the "hygiene hypothesis", biota alteration theory describes the effects of biota alteration on the human immune system. Work on this topic has pinpointed depletion of helminths as a key loss to the body's ecosystem in Western society, and suggests that some exposure to helminths, ubiquitous prior to the modern era, may be necessary for normal immune system development. Socio-medical studies of humans "self-treating" with helminths as well as limited studies in animal models strongly suggest that helminth therapy may be a productive approach toward treating a range of neuropsychiatric disorders, including chronic fatigue, migraine headaches, depression and anxiety disorders. However, helminth therapy faces some daunting hurdles, including the lack of a financial incentive for development, despite a tremendous potential market for the organisms. It is argued that benevolent donation for early trials as well as changes in regulatory policy to accommodate helminth therapy may be important for the field to develop. It is hoped that future success with some high-profile trials can propel the field, now dominated more by self-treatment than by clinical trials, forward into the main stream of medicine.

Evolution of the hygiene hypothesis into biota alteration theory: what are the paradigms and where are the clinical applications?

For thousands of years, changes in human cultures have altered the biota associated with the human body, and those alterations have strongly influenced human health. The hygiene hypothesis has evolved over the past 30 years into a nuanced biota alteration theory, but modern medical priorities and regulatory policies have resulted in tragic underutilization of the acquired knowledge.

Intestinal, but not hepatic, ChREBP is required for fructose tolerance.

Increased sugar consumption is a risk factor for the metabolic syndrome including obesity, hypertriglyceridemia, insulin resistance, diabetes, and nonalcoholic fatty liver disease (NAFLD). Carbohydrate responsive element-binding protein (ChREBP) is a transcription factor that responds to sugar consumption to regulate adaptive metabolic programs. Hepatic ChREBP is particularly responsive to fructose and global ChREBP-KO mice are intolerant to diets containing fructose. It has recently been suggested that ChREBP protects the liver from hepatotoxicity following high-fructose diets (HFrDs). We directly tested this hypothesis using tissue-specific ChREBP deletion. HFrD increased adiposity and impaired glucose homeostasis in control mice, responses that were prevented in liver-specific ChREBP-KO (LiChKO) mice. Moreover, LiChKO mice tolerated chronic HFrD without marked weight loss or hepatotoxicity. In contrast, intestine-specific ChREBP-KO (IChKO) mice rapidly lost weight after transition to HFrD, and this was associated with dilation of the small intestine and cecum, suggestive of malabsorption. These findings were associated with downregulation of the intestinal fructose transporter, Slc2a5, which is essential for fructose tolerance. Altogether, these results establish an essential role for intestinal, but not hepatic, ChREBP in fructose tolerance.

An overview of chemical inhibitors of the Nrf2-ARE signaling pathway and their potential applications in cancer therapy.

The Nuclear factor erythroid 2-related factor 2 (Nrf2) is a key transcription factor regulating a wide array of genes for antioxidant and detoxification enzymes in response to oxidative and xenobiotic stress. A large number of Nrf2-antioxidant response element (ARE) activators have been screened for use as chemopreventive agents in oxidative stress-related diseases and even cancer. However, constitutive activation of Nrf2 occurs in a variety of cancers. Aberrant activation of Nrf2 is correlated with cancer progression, chemoresistance, and radioresistance. In this review, we examine recent studies of Nrf2-ARE inhibitors in the context of cancer therapy. We enumerate the possible Nrf2-inhibiting mechanisms of these compounds, their effects sensitizing cancer cells to chemotherapeutic agents, and the prospect of applying them in clinical cancer therapy.