The Utility of Additional Imaging in Trauma Consults with Mild to Moderate Injury.

Limiting CT imaging in the ED has gained interest recently. After initial trauma workup for consultations in the ED, additional CT imaging is frequently ordered. We assessed the benefits of this additional imaging. Our hypothesis was that additional imaging in lower acuity trauma consults results in the diagnosis of new significant injuries with a change in treatment plan and increased Injury Severity Score (ISS). The registry at our Level I trauma center was queried from November 2015 to November 2016 for trauma consults initially evaluated by ED physicians. Patients with mild to moderate injuries were included. Injury findings before and after additional imaging were determined by chart review and pre- and postimaging ISS were calculated. Blinded trauma surgeons assessed the findings for clinical significance and changes in treatment. Four hundred and twenty-one patients were evaluated, 41 were excluded. One hundred and forty patients (37%) underwent additional CT imaging. Forty-seven patients (34%) had additional injuries found, with 16 (12%) increasing their ISS (mean 0.54, SD 1.66). Ninety-three per cent of cases resulted in at least one physician finding the new injuries clinically significant; however, agreement was low (κ = 0.095). For 70 per cent, at least one physician felt the findings warranted a change in treatment plan (κ = 0.405). Additional imaging in ED trauma consults resulted in the identification of new injuries in 1/3 of our patient sample. This suggests that current efforts to limit the use of CT imaging in trauma patients may result in significant injuries going undiscovered and undertreated. Further research is needed to determine the risk of attempts to limit imaging.

Parathyroid hormone as a marker for hypoperfusion in trauma: A prospective observational study.

BACKGROUND: Hyperparathyroidism is common in critical illness. Intact parathyroid hormone has a half-life of 3 minutes to 5 minutes due to rapid clearance by the liver, kidneys, and bone. In hemorrhagic shock, decreased clearance may occur, thus making parathyroid hormone a potential early marker for hypoperfusion. We hypothesized that early hyperparathyroidism predicts mortality and transfusion in trauma patients. METHODS: A prospective observational study was performed at a Level I trauma center in consecutive adult patients receiving the highest level of trauma team activation. Parathyroid hormone and lactic acid were added to the standard laboratory panel drawn in the trauma bay on arrival, before the administration of any blood products. The primary outcomes assessed were transfusion in 24 hours and mortality. RESULTS: Forty-six patients were included. Median age was 47 years, 82.6% were men, 15.2% suffered penetrating trauma, and 21.7% died. Patients who were transfused in the first 24 hours (n = 17) had higher parathyroid hormone (182.0 pg/mL vs. 73.5 pg/mL, p < 0.001) and lactic acid (4.6 pg/mL vs. 2.3 pg/mL, p = 0.001). Patients who did not survive to discharge (n = 10) also had higher parathyroid hormone (180.3 pg/mL vs. 79.3 pg/mL, p < 0.001) and lactic acid (5.5 mmol/L vs. 2.5 mmol/L, p = 0.001). For predicting transfusion in the first 24 hours, parathyroid hormone has an area under the receiver operating characteristic curve of 0.876 compared with 0.793 for lactic acid and 0.734 for systolic blood pressure. Parathyroid hormone has an area under the receiver operating characteristic curve of 0.875 for predicting mortality compared with 0.835 for lactic acid and 0.732 for systolic blood pressure. CONCLUSION: Hyperparathyroidism on hospital arrival in trauma patients predicts mortality and transfusion in the first 24 hours. Further research should investigate the value of parathyroid hormone as an endpoint for resuscitation. LEVEL OF EVIDENCE: Prognostic, level II.

NMDA receptor activation regulates sociability by its effect on mTOR signaling activity.

Tuberous Sclerosis Complex is one example of a syndromic form of autism spectrum disorder associated with disinhibited activity of mTORC1 in neurons (e.g., cerebellar Purkinje cells). mTORC1 is a complex protein possessing serine/threonine kinase activity and a key downstream molecule in a signaling cascade beginning at the cell surface with the transduction of neurotransmitters (e.g., glutamate and acetylcholine) and nerve growth factors (e.g., Brain-Derived Neurotrophic Factor). Interestingly, the severity of the intellectual disability in Tuberous Sclerosis Complex may relate more to this metabolic disturbance (i.e., overactivity of mTOR signaling) than the density of cortical tubers. Several recent reports showed that rapamycin, an inhibitor of mTORC1, improved sociability and other symptoms in mouse models of Tuberous Sclerosis Complex and autism spectrum disorder, consistent with mTORC1 overactivity playing an important pathogenic role. NMDA receptor activation may also dampen mTORC1 activity by at least two possible mechanisms: regulating intraneuronal accumulation of arginine and the phosphorylation status of a specific extracellular signal regulating kinase (i.e., ERK1/2), both of which are "drivers" of mTORC1 activity. Conceivably, the prosocial effects of targeting the NMDA receptor with agonists in mouse models of autism spectrum disorders result from their ability to dampen mTORC1 activity in neurons. Strategies for dampening mTORC1 overactivity by NMDA receptor activation may be preferred to its direct inhibition in chronic neurodevelopmental disorders, such as autism spectrum disorders.

NMDA receptors on the surface of cancer cells: target for chemotherapy?

The mammalian target of rapamycin (mTOR), a serine/threonine kinase, is a therapeutic target for many types of cancers. NMDA receptors regulate mTOR signalling activity; their inappropriate expression on several human cancer cell lines represents a potential therapeutic avenue to control dysregulated growth, division and invasiveness. Targeting these receptors with selective ligands (e.g., glycineB site ligands) may be a less toxic and more tolerable approach than administering compounds acting at the mTORC1 complex itself, such as rapamycin and its derivatives. Thus, testing glycineB site ligands in relevant in vitro and in vivo paradigms with established human cancer cells that express NMDA receptors on their surface could provide proofs of concept/principle that would encourage exploration of these and other "non-toxic" strategies. Interestingly, in some cancer models that express NMDA receptors on their surface, NMDA receptor antagonists, such as MK-801 (dizocilpine), were shown to possess anti-proliferative and anti-invasive effects, which conflict with hypotheses about promoting NMDA receptor activation as a cancer chemotherapeutic strategy. Whether NMDA receptor activation or antagonism is associated with anti-proliferative and anti-invasive effects may reflect differences between cancer cell lines in terms of the proteins associated with the NMDA receptors on their cell surfaces, which, in turn, could lead to different "downstream" effects on cascades of intracellular phosphorylations. Irrespective of whether activation or antagonism is associated with anti-proliferative and anti-invasive effects for specific types of cancer, data are emerging that support exploration of targeting NMDA receptors expressed on the surface of cancer cells as a therapeutic strategy.

Rapamycin improves sociability in the BTBR T(+)Itpr3(tf)/J mouse model of autism spectrum disorders.

Overactivation of the mammalian target of rapamycin (mTOR) has been implicated in the pathogenesis of syndromic forms of autism spectrum disorders (ASDs), such as tuberous sclerosis complex, neurofibromatosis 1, and fragile X syndrome. Administration of mTORC1 (mTOR complex 1) inhibitors (e.g. rapamycin) in syndromic mouse models of ASDs improved behavior, cognition, and neuropathology. However, since only a minority of ASDs are due to the effects of single genes (∼10%), there is a need to explore inhibition of mTOR activity in mouse models that may be more relevant to the majority of nonsyndromic presentations, such as the genetically inbred BTBR T(+)Itpr3(tf)/J (BTBR) mouse model of ASDs. BTBR mice have social impairment and exhibit increased stereotypic behavior. In prior work, d-cycloserine, a partial glycineB site agonist that targets the N-methyl-d-aspartate (NMDA) receptor, was shown to improve sociability in both Balb/c and BTBR mouse models of ASDs. Importantly, NMDA receptor activation regulates mTOR signaling activity. The current study investigated the ability of rapamycin (10mg/kg, i.p.×four days), an mTORC1 inhibitor, to improve sociability and stereotypic behavior in BTBR mice. Using a standard paradigm to assess mouse social behavior, rapamycin improved several measures of sociability in the BTBR mouse, suggesting that mTOR overactivation represents a therapeutic target that mediates or contributes to impaired sociability in the BTBR mouse model of ASDs. Interestingly, there was no effect of rapamycin on stereotypic behaviors in this mouse model.