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A growing body of evidence suggests that memories of fearful events may be altered after initial acquisition or learning. Although much of this work has been done in rodents using Pavlovian fear conditioning, it may have important implications for fear memories in humans such as in post-traumatic stress disorder (PTSD). A recent study suggested that cued fear memories, made labile by memory retrieval, were made additionally labile and thus more vulnerable to subsequent modification when mice inhaled 10% carbon dioxide (CO2) during retrieval. In light of this finding, we hypothesized that 10% CO2 inhalation soon after fear acquisition might affect memory recall 24 h later. We found that both cue and context fear memory were increased by CO2 exposure after fear acquisition. The effect of CO2 was time-dependent, as CO2 inhalation administered 1 or 4 h after cued fear acquisition increased fear memory, whereas CO2 inhalation 4 h before or 24 h after cued fear acquisition did not increase fear memory. The ability of CO2 exposure following acquisition to enhance fear memory was not a general consequence of stress, as restraining mice after acquisition did not alter cued fear memory. The memory-enhancing action of CO2 may be relatively specific to fear conditioning as novel object recognition was impaired by post-training CO2 inhalation. To explore the molecular underpinnings of these effects, we tested if they depended on the acid-sensing ion channel-1a (ASIC1A), a proton-gated cation channel that mediates other effects of CO2, likely via its ability to sense acidosis induced during CO2 inhalation. We found that CO2 inhalation did not alter cued or context fear memory in Asic1a–/– mice, suggesting that this phenomenon critically depends on ASIC1A. These results suggest that brain acidosis around the time of a traumatic event may enhance memory of the trauma, and may thus constitute an important risk factor for developing PTSD. Moreover, preventing peritraumatic acidosis might reduce risk of PTSD.

Aim Glucocorticoids play a major role in regulating the stress response, and an imbalance of glucocorticoids has been implicated in stress-related disorders. Within mouse models, CpGs across the genome have been shown to be differentially methylated in response to glucocorticoid treatment, and using the Infinium 27K array, it was shown that humans given synthetic glucocorticoids had DNA methylation (DNAm) changes in blood. However, further investigation of the extent to which glucocorticoids affect DNAm across a larger proportion of the genome is needed. Methods Buccal samples were collected before and after synthetic glucocorticoid treatment in the context of a dental procedure. This included 30 tooth extraction surgery patients who received 10 mg of dexamethasone. Genome-wide DNAm was assessed with the Infinium HumanMethylationEPIC array. Results Five CpGs showed genome-wide significant DNAm changes that were >10%. These differentially methylated CpGs were in or nearest the following genes: ZNF438, KLHDC10, miR-544 or CRABP1, DPH5, and WDFY2. Using previously published datasets of human blood gene expression changes following dexamethasone exposure, a significant proportion of genes with false-discovery-rate-adjusted significant CpGs were also differentially expressed. A pathway analysis of the genes with false-discovery-rate-adjusted significant CpGs revealed significant enrichment of olfactory transduction, pentose and glucuronate interconversions, ascorbate and aldarate metabolism, and steroid hormone biosynthesis pathways. Conclusion High-dose synthetic glucocorticoid administration in the setting of a dental procedure was significantly associated with DNAm changes within buccal samples. These findings are consistent with prior findings of an influence of glucocorticoids on DNAm in humans.

Aim Delirium is common and dangerous among elderly inpatients; yet, it is underdiagnosed and thus undertreated. This study aimed to test the diagnostic characteristics of a noninvasive point-of-care device with two-channel (bispectral) electroencephalography (EEG) for the screening of delirium in the hospital. Methods Patients admitted to the University of Iowa Hospitals and Clinics were assessed for the presence of delirium with a clinical assessment, the Confusion Assessment Method for Intensive Care Unit and Delirium Rating Scale. Subsequently, we obtained a 10-min bispectral EEG (BSEEG) recording from a hand-held electroencephalogram device during hospitalization. We performed power spectral density analysis to differentiate between those patients with and without delirium. Results Initially 45 subjects were used as a test dataset to establish a cut-off. The BSEEG index was determined to be a significant indicator of delirium, with sensitivity 80% and specificity 87.7%. An additional independent validation dataset with 24 patients confirmed the validity of the approach, with a sensitivity of 83.3% and specificity of 83.3%. Conclusion In this pilot study, the BSEEG method was able to distinguish delirious patients from non-delirious patients. Our data showed the feasibility of this technology for mass screening of delirium in the hospital.

Urine testing is routinely used for screening purposes in clinical practice. Indications for urine screening previously covered in this book are to assist in the diagnosis of various nephrologic and/or urologic diseases. Three other common uses include urine screens for substance use disorders, to confirm antipsychotic medication adherence and to identify sexually transmitted infections in at risk populations.

Some hospitalized patients with comorbid, chronic medical and psychiatric illnesses may benefit from admission to an integrated unit that can provide care for both conditions. This commentary descr...

BACKGROUND Delirium is common and dangerous, yet underdetected and undertreated. Current screening questionnaires are subjective and ineffectively implemented in busy hospital workflows. Electroencephalography (EEG) can objectively detect the diffuse slowing characteristic of delirium, but it is not suitable for high-throughput screening due to size, cost, and the expertise required for lead placement and interpretation. This study hypothesized that an efficient and reliable point-of-care EEG device for high-throughput screening could be developed. METHODS This prospective study, which measured bispectral EEG (BSEEG) from elderly inpatients to assess their outcomes, was conducted at the University of Iowa Hospitals and Clinics from January 2016 to October 2017. A BSEEG score was defined based on the distribution of 2,938 EEG recordings from the 428 subjects who were assessed for delirium; primary outcomes measured were hospital length of stay, discharge disposition, and mortality. RESULTS A total of 274 patients had BSEEG score data available for analysis. Delirium and BSEEG score had a significant association (P < .001). Higher BSEEG scores were significantly correlated with length of stay (P < .001 unadjusted, P = .001 adjusted for age, sex, and Charlson Comorbidity Index [CCI] score) as well as with discharge not to home (P < .01). Hazard ratio for survival controlling for age, sex, CCI score, and delirium status was 1.35 (95% CI,1.04 to 1.76; P = .025). CONCLUSIONS In BSEEG, an efficient and reliable device that provides an objective measurement of delirium status was developed. The BSEEG score is significantly associated with pertinent clinical outcomes of mortality, hospital length of stay, and discharge disposition. The BSEEG score better predicts mortality than does clinical delirium status. This study identified a previously unrecognized subpopulation of patients without clinical features of delirium who are at increased mortality risk.

Cerebral cavernous malformations are common vascular lesions of the central nervous system that predispose to seizures, focal neurologic deficits and potentially fatal hemorrhagic stroke. Human genetic studies have identified three genes associated with the disease and biochemical studies of these proteins have identified interaction partners and possible signaling pathways. A variety of animal models of CCM have been described to help translate the cellular and biochemical insights into a better understanding of disease mechanism. In this minireview, we discuss the contributions of animal models to our growing understanding of the biology of cavernous malformations, including the elucidation of the cellular context of CCM protein actions and the in vivo confirmation of abnormal endothelial cell-cell interactions. Challenges and progress towards developing a faithful model of CCM biology are reviewed.

Neurolymphomatosis (NL) is a rare condition associated with lymphomas in which various structures of the nervous system are infiltrated by malignant lymphocytes. Rarely, it may be the presenting feature of recurrence of lymphoma otherwise deemed to be in remission. It is crucial, as is the case with all types of nodal or visceral involvement of lymphoma, to identify the disease early and initiate treatment with chemotherapy and/or radiation therapy. Positron emission tomography-computed tomography (PET-CT) has been shown to be a sensitive modality for staging, restaging, biopsy guidance, therapy response assessment, and surveillance for recurrence of lymphoma. Magnetic resonance imaging (MRI) is another useful imaging modality, which, along with PET/CT, compliment cerebrospinal spinal fluid (CSF) cytology and electromyography (EMG) in the diagnosis of NL. Performing nerve biopsies to confirm neurolymphomatosis can be challenging and with associated morbidity. The case presented herein illustrates the practical usefulness of these tests in detecting NL as a heralding feature of lymphoma recurrence, especially in the absence of histopathologic correlation.

Molting is required for progression between larval stages in the life cycle of nematodes. We have identified four mutant alleles of a Caenorhabditis elegans metalloprotease gene, nas-37, that cause incomplete ecdysis. At each molt the cuticle fails to open sufficiently at the anterior end and the partially shed cuticle is dragged behind the animal. The gene is expressed in hypodermal cells 4 hours before ecdysis during all larval stages. The NAS-37 protein accumulates in the anterior cuticle and is shed in the cuticle after ecdysis. This pattern of protein accumulation places NAS-37 in the right place and at the right time to degrade the cuticle to facilitate ecdysis. The nas-37 gene has orthologs in other nematode species,including parasitic nematodes, and they undergo a similar shedding process. For example, Haemonchus contortus molts by digesting a ring of cuticle at the tip of the nose. Incubating Haemonchus larvae in extracted exsheathing fluids causes a refractile ring of digested cuticle to form at the tip of the nose. When Haemonchus cuticles are incubated with purified NAS-37, a similar refractile ring forms. NAS-37 degradation of the Haemonchus cuticle suggests that the metalloproteases and the cuticle substrates involved in exsheathment of parasitic nematodes are conserved in free-living nematodes.

Cerebral cavernous malformation (CCM) is a disease of vascular malformations known to be caused by mutations in one of three genes: CCM1, CCM2 or CCM3. Despite several studies, the mechanism of CCM lesion onset remains unclear. Using a Ccm1 knockout mouse model, we studied the morphogenesis of early lesion formation in the retina in order to provide insight into potential mechanisms. We demonstrate that lesions develop in a stereotypic location and pattern, preceded by endothelial hypersprouting as confirmed in a zebrafish model of disease. The vascular defects seen with loss of Ccm1 suggest a defect in endothelial flow response. Taken together, these results suggest new mechanisms of early CCM disease pathogenesis and provide a framework for further study.

The innate immune system provides a first line of defense against invading pathogens by releasing multiple inflammatory cytokines, such as interleukin-1beta and tumor necrosis factor-alpha, which directly combat the infectious agent and recruit additional immune responses. This exuberant cytokine release paradoxically injures the host by triggering leakage from capillaries, tissue edema, organ failure, and shock. Current medical therapies target individual pathogens with antimicrobial agents or directly either blunt or boost the host's immune system. We explored a third approach: activating with the soluble ligand Slit an endothelium-specific, Robo4-dependent signaling pathway that strengthens the vascular barrier, diminishing deleterious aspects of the host's response to the pathogen-induced cytokine storm. This approach reduced vascular permeability in the lung and other organs and increased survival in animal models of bacterial endotoxin exposure, polymicrobial sepsis, and H5N1 influenza. Thus, enhancing the resilience of the host vascular system to the host's innate immune response may provide a therapeutic strategy for treating multiple infectious agents.

Corrigendum: The cerebral cavernous malformation signaling pathway promotes vascular integrity via Rho GTPases