A 60-Year-Old Man With Dyspnea, Proximal Muscle Weakness, and Pulmonary Arterial Hypertension.

CASE PRESENTATION: A 60-year-old man with no significant medical history presented to the pulmonology clinic with 2 years of progressive weakness and shortness of breath. Showering and other activities of daily living caused him significant fatigue and dyspnea. He had a 20-pack-year smoking history, but no significant history of alcohol or illicit drug use. He did not take any prescribed or over-the-counter medications for chronic medical conditions and had never been on statin therapy. Vital signs were significant for an oxygen saturation of 91% on 4-L nasal cannula. He required up to 6 L of oxygen during a walk test. Physical examination showed mild inspiratory crackles in the lung bases, loud splitting of the second pulmonic valve (P2) with a right parasternal heave, and 2+ pitting edema in the lower extremities. There was muscle weakness, pain, and wasting of the proximal upper and lower extremities, particularly in his legs. He denied any joint pain, and there was no evidence of rash or dysphagia.

Gulf War veterans exhibit broadband sleep EEG power reductions in regions overlying the frontal lobe.

AIMS: Nearly a third of U.S. veterans who deployed in support of the 1990-1991 Persian Gulf War are affected by Gulf War illness (GWI). Here we aimed to characterize whether subjective sleep complaints in GWI veterans are associated with objective sleep EEG disturbances relative to healthy veterans and controls; and whether Gulf War veterans show alterations in neural activity during sleep that differentiate them from healthy subjects. MAIN METHODS: We used high-density EEG (HDEEG) to assess regional patterns of rapid eye movement (REM) sleep and non-REM (NREM) sleep between three groups: Gulf War male veterans with fatigue and GWI, Gulf War male veterans without fatigue or GWI, and control males. The groups were matched relative to age, sex and obstructive sleep apnea. Topographic comparisons of nocturnal NREM and REM sleep were made between groups for all frequency bands. KEY FINDINGS: Topographic analysis revealed a broadband reduction in EEG power in a circumscribed region overlying the frontal lobe in both groups of Gulf War veterans, regardless of GWI and fatigue. This frontal reduction in neural activity was present, to some extent, across all frequency bands in NREM and REM sleep. SIGNIFICANCE: Given that our findings were observed in all Gulf War veterans, it appears unlikely that frontal sleep HDEEG power reductions prove wholly responsible for fatigue symptoms. These results provide avenues for research which may someday contribute to improved clinical care of formerly deployed veterans of the Persian Gulf War.

Local Sleep Slow-Wave Activity Colocalizes With the Ictal Symptomatogenic Zone in a Patient With Reflex Epilepsy: A High-Density EEG Study.

Background: Slow-wave activity (SWA) during non-rapid eye movement (NREM) sleep reflects synaptic potentiation during preceding wakefulness. Epileptic activity may induce increases in state-dependent SWA in human brains, therefore, localization of SWA may prove useful in the presurgical workup of epileptic patients. We analyzed high-density electroencephalography (HDEEG) data across vigilance states from a reflex epilepsy patient with a clearly localizable ictal symptomatogenic zone to provide a proof-of-concept for the testability of this hypothesis. Methods: Overnight HDEEG recordings were obtained in the patient during REM sleep, NREM sleep, wakefulness, and during a right facial motor seizure then compared to 10 controls. After preprocessing, SWA (i.e., delta power; 1-4 Hz) was calculated at each channel. Scalp level and source reconstruction analyses were computed. We assessed for statistical differences in maximum SWA between the patient and controls within REM sleep, NREM sleep, wakefulness, and seizure. Then, we completed an identical statistical comparison after first subtracting intrasubject REM sleep SWA from that of NREM sleep, wakefulness, and seizure SWA. Results: The topographical analysis revealed greater left hemispheric SWA in the patient vs. controls in all vigilance states except REM sleep (which showed a right hemispheric maximum). Source space analysis revealed increased SWA in the left inferior frontal cortex during NREM sleep and wakefulness. Ictal data displayed poor source-space localization. Comparing each state to REM sleep enhanced localization accuracy; the most clearly localizing results were observed when subtracting REM sleep from wakefulness. Conclusion: State-dependent SWA during NREM sleep and wakefulness may help to identify aspects of the potential epileptogenic zone. Future work in larger cohorts may assess the clinical value of sleep SWA to help presurgical planning.

A 58-Year-Old Man With Acute Encephalopathy, Fever, and Multi-Organ Dysfunction.

CASE PRESENTATION: A 58-year-old man with a medical history of type 2 diabetes mellitus and COPD presented with fever, chills, nausea, vomiting, left upper quadrant abdominal pain, and altered mental status for the past week. His mental status rapidly deteriorated and work of breathing increased, which required intubation and mechanical ventilation. The patient's wife reported recent exposure to tick bites after finding several ticks while changing the sheets in their bedroom.

A biventricular takotsubo cardiomyopathy complication: large thrombus formation to stroke in 150 min.

A 67-year-old postmenopausal African American woman presented with biventricular takotsubo cardiomyopathy (TTC)-evidenced by transthoracic echocardiography (TTE) showing apical akinesis of both left and right ventricles in the absence of obstructive coronary artery disease on left heart catheterisation. On the 4th hospital day, she experienced acute left facial droop, dysarthria and dysphagia. CT of the head showed a wedge infarct of the right middle cerebral artery territory. Cardioembolism was presumed after intracranial and extracranial sources of thromboembolism were ruled out. Intravenous tissue plasminogen activator (tPA) was administered with resolution of symptoms. She was later discharged without neurological deficits. Crucially, repeat TTE after tPA infusion revealed a left ventricular mass concerning for thrombus. TTE 150 min prior to stroke onset was devoid of a mass. This case uniquely illustrates the potential for rapid thrombus formation and embolism in patients with TTC. As such, it emphasises the high index of suspicion required for management of these patients.

Validation of the 2HELPS2B Seizure Risk Score in Acute Brain Injury Patients.

BACKGROUND AND OBJECTIVE: Seizures are common after traumatic brain injury (TBI), aneurysmal subarachnoid hemorrhage (aSAH), subdural hematoma (SDH), and non-traumatic intraparenchymal hemorrhage (IPH)-collectively defined herein as acute brain injury (ABI). Most seizures in ABI are subclinical, meaning that they are only detectable with EEG. A method is required to identify patients at greatest risk of seizures and thereby in need of prolonged continuous EEG monitoring. 2HELPS2B is a simple point system developed to address this need. 2HELPS2B estimates seizure risk for hospitalized patients using five EEG findings and one clinical finding (pre-EEG seizure). The initial 2HELPS2B study did not specifically assess the ABI subpopulation. In this study, we aim to validate the 2HELPS2B score in ABI and determine its relative predictive accuracy compared to a broader set of clinical and electrographic factors. METHODS: We queried the Critical Care EEG Monitoring Research Consortium database for ABI patients age ≥ 18 with > 6 h of continuous EEG monitoring; data were collected between February 2013 and November 2018. The primary outcome was electrographic seizure. Clinical factors considered were age, coma, encephalopathy, ABI subtype, and acute suspected or confirmed pre-EEG clinical seizure. Electrographic factors included 18 EEG findings. Predictive accuracy was assessed using a machine-learning paradigm with area under the receiver operator characteristic (ROC) curve as the primary outcome metric. Three models (clinical factors alone, EEG factors alone, EEG and clinical factors combined) were generated using elastic-net logistic regression. Models were compared to each other and to the 2HELPS2B model. All models were evaluated by calculating the area under the curve (AUC) of a ROC analysis and then compared using permutation testing of AUC with bootstrapping to generate confidence intervals. RESULTS: A total of 1528 ABI patients were included. Total seizure incidence was 13.9%. Seizure incidence among ABI subtype varied: IPH 17.2%, SDH 19.1%, aSAH 7.6%, TBI 9.2%. Age ≥ 65 (p = 0.015) and pre-cEEG acute clinical seizure (p < 0.001) positively affected seizure incidence. Clinical factors AUC = 0.65 [95% CI 0.60-0.71], EEG factors AUC = 0.82 [95% CI 0.77-0.87], and EEG and clinical factors combined AUC = 0.84 [95% CI 0.80-0.88]. 2HELPS2B AUC = 0.81 [95% CI 0.76-0.85]. The 2HELPS2B AUC did not differ from EEG factors (p = 0.51), or EEG and clinical factors combined (p = 0.23), but was superior to clinical factors alone (p < 0.001). CONCLUSIONS: Accurate seizure risk forecasting in ABI requires the assessment of EEG markers of pathologic electro-cerebral activity (e.g., sporadic epileptiform discharges and lateralized periodic discharges). The 2HELPS2B score is a reliable and simple method to quantify these EEG findings and their associated risk of seizure.

Race, insurance status, and traumatic brain injury outcomes before and after enactment of the Affordable Care Act.

BACKGROUND: The Affordable Care Act aims to improve patient outcomes. Race/ethnicity and insurance status impact outcomes after traumatic brain injury. We sought to gauge the Affordable Care Act's effect on outcomes after traumatic brain injury, as graded by race/ethnicity and insurance status. METHODS: The National Trauma Data Bank was utilized to identify traumatic brain injury patients before and after the Affordable Care Act. Patient outcomes comprised of hospital duration of stay, in-hospital mortality, discharge to rehabilitation, and surgical procedures. Using regression analysis, we evaluated the impact of race/ethnicity and insurance status on traumatic brain injury outcomes, then compared them before and after the Affordable Care Act. RESULTS: Mortality decreased for blacks (odds ratio = 0.96 [confidence interval 0.83-1.10] to odds ratio = 0.79 [confidence interval = 0.70-0.89], and Hispanics (odds ratio = 1.03 [confidence interval = 0.90-1.17] to odds ratio = 0.79 [confidence interval = 0.70-0.89]). Mortality increased for the uninsured (odds ratio = 1.28 [confidence interval = 1.11-1.47] to odds ratio = 1.40 [confidence interval = 1.24-1.58]). Medicaid patients underwent decreased duration of stay, (coefficient = 2.75 [confidence interval = 2.49-3.02] to coefficient = 2.17, [confidence interval = 1.98-2.37]), discharge to rehabilitation (odds ratio = 1.15, [confidence interval = 1.04-1.26] to odds ratio = 0.95 [confidence interval = 0.87-1.03]), and surgical procedures (odds ratio = 1.28 [confidence interval = 1.13-1.45] to odds ratio = 1.18, [confidence interval = 1.07-1.30]), while mortality remained unchanged. CONCLUSION: After the Affordable Care Act traumatic brain injury mortality decreased for blacks and Hispanics, but increased for the uninsured. Decreasing trends in resource consumption were also evident, especially for Medicaid patients. These results may illustrate altered delivery of care.

Regulation of late cornified envelope genes relevant to psoriasis risk by plant-derived cyanidin.

The PSORS4 genetic risk factor for psoriasis is a deletion of two late cornified envelope (LCE) genes (LCE3C_LCE3Bdel) in a cluster of five LCE3 genes with a proposed role in skin repair. We previously showed that 1,25-dihydroxyvitamin D3 (1,25D) modestly upregulates transcripts from all five LCE3 genes as monitored by real time PCR in primary human keratinocytes. Herein we report that cyanidin, a plant-derived compound with anti-inflammatory/anti-oxidant properties, upregulates expression of all five LCE3 genes in cultures of differentiating primary human keratinocytes to a greater extent that does 1,25D. This action of cyanidin is dependent on the differentiation state of the keratinocytes, with a stronger effect after the cells have been incubated with 1.2mM calcium for 24h. Competition displacement assays using radiolabeled 1,25D revealed that cyanidin directly competes as a ligand for vitamin D receptor (VDR) binding with an estimated IC50 of 500µM. However, 20µM cyanidin is sufficient to upregulate LCE3 genes. The 25-fold discrepancy between the cyanidin concentration required for upregulating LCE3 genes in intact keratinocytes vs. that required for direct binding to VDR in vitro suggests that cyanidin may be: (a) metabolized to a more active VDR ligand in keratinocytes and/or (b) functioning via a non-VDR mediated mechanism. The fact that cyanidin is the most potent upregulator of global LCE3 gene expression reported to date suggests that this or related compounds may have potential in psoriasis therapy.

The nuclear vitamin D receptor controls the expression of genes encoding factors which feed the "Fountain of Youth" to mediate healthful aging.

The nuclear vitamin D receptor (VDR) binds 1,25-dihydroxyvitamin D3 (1,25D), its high affinity renal endocrine ligand, to signal intestinal calcium and phosphate absorption plus bone remodeling, generating a mineralized skeleton free of rickets/osteomalacia with a reduced risk of osteoporotic fractures. 1,25D/VDR signaling regulates the expression of TRPV6, BGP, SPP1, LRP5, RANKL and OPG, while achieving feedback control of mineral ions to prevent age-related ectopic calcification by governing CYP24A1, PTH, FGF23, PHEX, and klotho transcription. Vitamin D also elicits numerous intracrine actions when circulating 25-hydroxyvitamin D3, the metabolite reflecting vitamin D status, is converted to 1,25D locally by extrarenal CYP27B1, and binds VDR to promote immunoregulation, antimicrobial defense, xenobiotic detoxification, anti-inflammatory/anticancer actions and cardiovascular benefits. VDR also affects Wnt signaling through direct interaction with beta-catenin, ligand-dependently blunting beta-catenin mediated transcription in colon cancer cells to attenuate growth, while potentiating beta-catenin signaling via VDR ligand-independent mechanisms in osteoblasts and keratinocytes to function osteogenically and as a pro-hair cycling receptor, respectively. Finally, VDR also drives the mammalian hair cycle in conjunction with the hairless corepressor by repressing SOSTDC1, S100A8/S100A9, and PTHrP. Hair provides a shield against UV-induced skin damage and cancer in terrestrial mammals, illuminating another function of VDR that facilitates healthful aging.

Curcumin: a novel nutritionally derived ligand of the vitamin D receptor with implications for colon cancer chemoprevention.

The nuclear vitamin D receptor (VDR) mediates the actions of 1,25-dihydroxyvitamin D(3) (1,25D) to regulate gene transcription. Recently, the secondary bile acid, lithocholate (LCA), was recognized as a novel VDR ligand. Using reporter gene and mammalian two-hybrid systems, immunoblotting, competitive ligand displacement and quantitative real-time PCR, we identified curcumin (CM), a turmeric-derived bioactive polyphenol, as a likely additional novel ligand for VDR. CM (10(-5) M) activated transcription of a luciferase plasmid containing the distal vitamin D responsive element (VDRE) from the human CYP3A4 gene at levels comparable to 1,25D (10(-8) M) in transfected human colon cancer cells (Caco-2). While CM also activated transcription via a retinoid X receptor (RXR) responsive element, activation of the glucocorticoid receptor (GR) by CM was negligible. Competition binding assays with radiolabeled 1,25D confirmed that CM binds directly to VDR. In mammalian two-hybrid assays employing transfected Caco-2 cells, CM (10(-5) M) increased the ability of VDR to recruit its heterodimeric partner, RXR, and steroid receptor coactivator-1 (SRC-1). Real-time PCR studies revealed that CM-bound VDR can activate VDR target genes CYP3A4, CYP24, p21 and TRPV6 in Caco-2 cells. Numerous studies have shown chemoprotection by CM against intestinal cancers via a variety of mechanisms. Small intestine and colon are important VDR-expressing tissues where 1,25D has known anticancer properties that may, in part, be elicited by activation of CYP-mediated xenobiotic detoxification and/or up-regulation of the tumor suppressor p21. Our results suggest the novel hypothesis that nutritionally-derived CM facilitates chemoprevention via direct binding to, and activation of, VDR.