Abstract Clinical studies have indicated an association between acute hyperglycemia and poor outcomes in patients with traumatic brain injury (TBI), although optimal blood glucose levels needed to ...maximize outcomes for these patients' remain under investigation. Previous results from experimental animal models suggest that post-TBI hyperglycemia may be harmful, neutral, or beneficial. The current studies determined the effects of single or multiple episodes of acute hyperglycemia on cerebral glucose metabolism and neuronal injury in a rodent model of unilateral controlled cortical impact (CCI) injury. In Experiment 1 , a single episode of hyperglycemia (50% glucose at 2 g/kg, i.p.) initiated immediately after CCI was found to significantly attenuate a TBI-induced depression of glucose metabolism in cerebral cortex (4 of 6 regions) and subcortical regions (2 of 7) as well as to significantly reduce the number of dead/dying neurons in cortex and hippocampus at 24 h post-CCI. Experiment 2 examined effects of more prolonged and intermittent hyperglycemia induced by glucose administrations (2 g/kg, i.p.) at 0, 1, 3 and 6 h post-CCI. The latter study also found significantly improved cerebral metabolism (in 3 of 6 cortical and 3 of 7 subcortical regions) and significant neuroprotection in cortex and hippocampus 1 day after CCI and glucose administration. These results indicate that acute episodes of post-TBI hyperglycemia can be beneficial and are consistent with other recent studies showing benefits of providing exogenous energy substrates during periods of increased cerebral metabolic demand.
Notch signaling plays an important role in developmental processes and adult tissue homeostasis. Altered Notch signaling has been associated with various diseases including cancer. While the ...importance of altered Notch signaling in cancers of hematopoietic and epithelial origins has been established, its role in tumors of mesenchymal origin is less clear. Here, we report that human osteosarcoma cell lines and primary human osteosarcoma tumor samples show significant up-regulation of Notch, its target genes and Osterix. Notch inhibition by γ-secretase inhibitors or by using lentiviral mediated expression of dominant negative Mastermind-like protein (DN-MAML) decreases osteosarcoma cell proliferation in vitro. In vivo, established human tumor xenografts in nude mice show decreased tumor growth after chemical or genetic inhibition of Notch signaling. Finally, transcriptional profiling of osteosarcomas from p53 mutant mice confirmed up-regulation of Notch1 target genes Hes1, Hey1 and its ligand Dll4. Our data suggest that activation of Notch signaling contributes to the pathogenesis of human osteosarcomas and its inhibition may be a therapeutic approach for the treatment of this mesenchymal tumor.
To provide a detailed semiology to aid the clinical recognition of psychogenic pseudosyncope (PPS), which concerns episodes of apparent transient loss of consciousness (TLOC) that mimic syncope.
We ...analyzed all consecutive tilt-table tests from 2006 to 2012 showing proven PPS, i.e., apparent TLOC had occurred without EEG changes or a decrease in heart rate (HR) or blood pressure (BP). We analyzed baseline characteristics, video data, EEG, ECG, and continuous BP measurements on a 1-second time scale. Data were compared with those of 69 cases of tilt-induced vasovagal syncope (VVS).
Of 800 tilt-table tests, 43 (5.4%) resulted in PPS. The majority (74%) were women. The median duration of apparent TLOC was longer in PPS (44 seconds) than in VVS (20 seconds, p < 0.05). During the event, the eyes were closed in 97% in PPS but in only 7% in VVS (p < 0.0001). A sudden head drop or moving down the tilt table was more common in PPS than in VVS (p < 0.01), but jerking movements occurred more frequently in VVS (p < 0.0001). In PPS, both HR and BP increased before and during apparent TLOC (p < 0.0001).
PPS is clinically distinct from VVS and can be diagnosed accurately with tilt-table testing and simultaneous EEG monitoring. Compared with VVS, eye closure during the event, long periods of apparent TLOC, and high HR and BP are highly specific for PPS. Improved understanding of the semiology of PPS as a clinical entity is vital to ensure accurate diagnosis.
Background Ambulatory blood pressure (BP) monitoring has long been used to monitor BP in hypertension and lately emerged as a useful tool to detect hypotensive susceptibility in reflex syncope. ...However, hemodynamic characteristics in reflex syncope have not been sufficiently explored. The present study investigated the differences between ambulatory BP monitoring profiles associated with reflex syncope and normal population. Methods and Results This is an observational study comparing ambulatory BP monitoring data from 50 patients with reflex syncope and 100 controls without syncope, age- and sex-matched 1:2. Mean 24-hour systolic (SBP) and diastolic BP, pulse pressure (24-hour PP), dipping status, and number of daytime SBP drops <90 to 100 mm Hg were analyzed. Variables associated with reflex syncope were investigated using multivariable logistic regression. Patients with reflex syncope displayed significantly lower 24-hour SBP (112.9±12.6 versus 119.3±11.5 mm Hg,
=0.002), higher 24-hour diastolic BP (85.2±9.6 versus 79.1±10.6 mm Hg,
<0.001), and markedly lower 24-hour PP (27.7±7.6 versus 40.3±9.0 mm Hg,
<0.001) compared with controls. Daytime SBP drops <90 mm Hg were more prevalent in patients with syncope (44% versus 17%,
<0.001). Daytime SBP drops <90 mm Hg, 24-hour PP <32 mm Hg, 24-hour SBP ≤110 mm Hg, and 24-hour diastolic BP ≥82 mm Hg were independently associated with reflex syncope, with 24-hour PP <32 mm Hg achieving the highest sensitivity (80%) and specificity (86%). Conclusions Patients with reflex syncope have lower 24-hour SBP but higher 24-hour diastolic BP and more frequent daytime SBP drops <90 mm Hg than individuals without syncope. Our results support the presence of lower SBP and PP in reflex syncope and suggest a role for ambulatory BP monitoring in the diagnostic work-up of this condition.
In this work, we present a perspective on the role machine intelligence can play in supporting human abilities. In particular, we consider research in rehabilitation technologies such as prosthetic ...devices, as this domain requires tight coupling between human and machine. Taking an agent-based view of such devices, we propose that human–machine collaborations have a capacity to perform tasks which is a result of the combined agency of the human and the machine. We introduce
communicative capital
as a resource developed by a human and a machine working together in ongoing interactions. Development of this resource enables the partnership to eventually perform tasks at a capacity greater than either individual could achieve alone. We then examine the benefits and challenges of increasing the agency of prostheses by surveying literature which demonstrates that building communicative resources enables more complex, task-directed interactions. The viewpoint developed in this article extends current thinking on how best to support the functional use of increasingly complex prostheses, and establishes insight toward creating more fruitful interactions between humans and supportive, assistive, and augmentative technologies.
The temporal-difference (TD) algorithm from reinforcement learning provides a simple method for incrementally learning predictions of upcoming events. Applied to classical conditioning, TD models ...suppose that animals learn a real-time prediction of the unconditioned stimulus (US) on the basis of all available conditioned stimuli (CSs). In the TD model, similar to other error-correction models, learning is driven by prediction errors—the difference between the change in US prediction and the actual US. With the TD model, however, learning occurs continuously from moment to moment and is not artificially constrained to occur in trials. Accordingly, a key feature of any TD model is the assumption about the representation of a CS on a moment-to-moment basis. Here, we evaluate the performance of the TD model with a heretofore unexplored range of classical conditioning tasks. To do so, we consider three stimulus representations that vary in their degree of temporal generalization and evaluate how the representation influences the performance of the TD model on these conditioning tasks.
Abstract
Aim of this study was to explore whether differences in resting hemodynamic parameters may be associated with tilt test results in unexplained syncope. We analyzed age, gender, systolic ...(SBP), diastolic blood pressure (DBP) and heart rate (HR) by merging three large databases of patients considered likely to be of vasovagal reflex etiology, comparing patients who had tilt-induced reflex response with those who did not. Tilt-induced reflex response was defined as spontaneous symptom reproduction with characteristic hypotension and bradycardia. Relationship of demographics and baseline supine BP to tilt-test were assessed using logistic regression models. Individual records of 5236 patients (45% males; mean age: 60 ± 22 years; 32% prescribed antihypertensive therapy) were analyzed. Tilt-positive (n = 3129, 60%) vs tilt-negative patients had lower SBP (127.2 ± 17.9 vs 129.7 ± 18.0 mmHg, p < 0.001), DBP (76.2 ± 11.5 vs 77.7 ± 11.7 mmHg, p < 0.001) and HR (68.0 ± 11.5 vs 70.5 ± 12.5 bpm, p < 0.001). In multivariable analyses, tilt-test positivity was independently associated with younger age (Odds ratio (OR) per 10 years:1.04; 95% confidence interval (CI), 1.01–1.07, p = 0.014), SBP ≤ 128 mmHg (OR:1.27; 95%CI, 1.11–1.44, p < 0.001), HR ≤ 69 bpm (OR:1.32; 95%CI, 1.17–1.50, p < 0.001), and absence of hypertension (OR:1.58; 95%CI, 1.38–1.81, p < 0.001). In conclusion, among patients with suspected reflex syncope, younger age, lower blood pressure and lower heart rate are associated with positive tilt-test result.
Orthostatic hypotension (OH) is a major sign of cardiovascular autonomic failure leading to orthostatic intolerance and syncope. Orthostatic hypotension is traditionally divided into classical OH ...(cOH) and delayed OH (dOH), but the differences between the two variants are not well-studied. We performed a systematic clinical and neuroendocrine characterization of OH patients in a tertiary syncope unit.
Among 2,167 consecutive patients (1,316 women, 60.7%; age, 52.6 ± 21.0 years) evaluated for unexplained syncope and severe orthostatic intolerance with standardized cardiovascular autonomic tests including head-up tilt (HUT), we identified those with a definitive diagnosis of cOH and dOH. We analyzed patients' history, clinical characteristics, hemodynamic variables, and plasma levels of epinephrine, norepinephrine, C-terminal-pro-arginine-vasopressin (CT-proAVP), C-terminal-endothelin-1, mid-regional-fragment of pro-atrial-natriuretic-peptide and pro-adrenomedullin in the supine position and at 3-min HUT.
We identified 248 cOH and 336 dOH patients (27% of the entire cohort); 111 cOH and 152 dOH had blood samples collected in the supine position and at 3-min HUT. Compared with dOH, cOH patients were older (68 vs. 60 years,
< 0.001), more often male (56.9 vs. 39.6%,
< 0.001), had higher systolic blood pressure (141 vs. 137 mmHg,
= 0.05), had lower estimated glomerular filtration rate (73 vs. 80 ml/min/1.73 m
,
= 0.003), more often pathologic Valsalva maneuver (86 vs. 49 patients,
< 0.001), pacemaker-treated arrhythmia (5 vs. 2%,
= 0.04), Parkinson's disease (5 vs. 1%,
= 0.008) and reported less palpitations before syncope (16 vs. 29%,
= 0.001). Supine and standing levels of CT-proAVP were higher in cOH (
= 0.022 and
< 0.001, respectively), whereas standing norepinephrine was higher in dOH (
= 0.001). After 3-min HUT, increases in epinephrine (
< 0.001) and CT-proAVP (
= 0.001) were greater in cOH, whereas norepinephrine increased more in dOH (
= 0.045).
One-quarter of patients with unexplained syncope and severe orthostatic intolerance present orthostatic hypotension. Classical OH patients are older, more often have supine hypertension, pathologic Valsalva maneuver, Parkinson's disease, pacemaker-treated arrhythmia, and lower glomerular filtration rate. Classical OH is associated with increased vasopressin and epinephrine during HUT, but blunted increase in norepinephrine.
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