BACKGROUND: Thrombin generation (TG) is a pivotal process in achieving hemostasis. Coagulation profiles during pregnancy and early neonatal period are different from that of normal (non-pregnant) adults. In this ex vivo study, the differences in TG in maternal and cord plasma relative to normal adult plasma were studied.
METHODS: Twenty consented pregnant women and ten consented healthy adults were included in the study. Maternal and cord blood samples were collected at the time of delivery. Platelet-poor plasma was isolated for the measurement of TG. In some samples, anti-FIXa aptamer, RB006, or a TFPI inhibitor, BAX499 were added to elucidate the contribution of intrinsic and extrinsic pathway to TG. Additionally, procoagulant and inhibitor levels were measured in maternal and cord plasma, and these values were used to mathematically simulate TG.
RESULTS: Peak TG was increased in maternal plasma (393.6±57.9 nM) compared to adult and cord samples (323.2±38.9 nM and 209.9±29.5 nM, respectively). Inhibitory effects of RB006 on TG were less robust in maternal or cord plasma (52% vs. 12% respectively) than in adult plasma (81%). Likewise the effectiveness of BAX499 as represented by the increase in peak TG was much greater in adult (21%) than in maternal (10%) or cord plasma (12%). Further, BAX499 was more effective in reversing RB006 in adult plasma than in maternal or cord plasma. Ex vivo data were reproducible with the results of the mathematical simulation of TG.
CONCLUSION: Normal parturient plasma shows a large intrinsic pathway reserve for TG compared to adult and cord plasma, while TG in cord plasma is sustained by extrinsic pathway, and low levels of TFPI and AT.
Heparanase is a heparan sulfate degrading endoglycosidase. Previous work has demonstrated that heparanase plays important roles in various biological processes including angiogenesis, wound healing and metastasis. However, the role of heparanase in the post-ischemic brain is not well defined. Transient focal cerebral ischemia in adult mice was induced by ligations of the right middle cerebral artery (MCA) and both common carotid arteries (CCAs). All mice were subjected to bromodeoxyuridine (BrdU) injection and sacrificed at different time points after stroke for immunohistochemical and Western blot analyses. Heparanase expression increased after ischemia in both cell-specific and time-dependent manners. Three to 7 days after stroke, levels of the 50-kD heparanase, basic fibroblast growth factor (FGF-2), and angiopoietin-2 (Ang-2) increased in the peri-infarct region. At early time points, heparanase expression was largely confined to proliferating vascular endothelial cells. At 14 days after ischemia, this expression had shifted to astrocytes in the same region. These data show that cerebral ischemia markedly increases heparanase levels in endothelial cells and then in astrocytes. The unique features of the heparanase upregulation imply that heparanase may play specific roles in the pathological and regenerative processes during the acute and sub-acute/chronic phase in the post-stroke brain.
by
Arun Ganesh;
Muhammad Qadri;
Richard L. Boortz-Marx;
Sana M. Al-Khatib;
David H. Harpole Jr;
Jason N. Katz;
Jason I. Koontz;
Joseph P. Mathew;
Neil D. Ray;
Albert Y. Sun;
Betty C. Tong;
Luis Ulloa;
Jonathan P. Piccini;
Marat Fudim
Purpose of Review
To highlight the indications, procedural considerations, and data supporting the use of stellate ganglion blockade (SGB) for management of refractory ventricular arrhythmias.
Recent Findings
In patients with refractory ventricular arrhythmias, unilateral or bilateral SGB can reduce arrhythmia burden and defibrillation events for 24–72 h, allowing time for use of other therapies like catheter ablation, surgical sympathectomy, or heart transplantation. The efficacy of SGB appears to be consistent despite the type (monomorphic vs polymorphic) or etiology (ischemic vs non-ischemic cardiomyopathy) of the ventricular arrhythmia. Ultrasound-guided SGB is safe with low risk for complications, even when performed on anticoagulation.
Summary
SGB is effective and safe and could be considered for patients with refractory ventricular arrhythmias.
BACKGROUND: Sugammadex rapidly reverses deep neuromuscular blockade, but owing to cost, questions remain about its optimal utilization. After the unrestricted introduction of sugammadex at Emory University Hospital, we hypothesized that reductions would be demonstrated in the primary outcome of post-anesthesia care unit (PACU) mechanical ventilation (MV) and secondary outcomes of PACU length of stay (LOS) and emergence time (surgery end to anesthesia end time in the PACU). METHODS: This retrospective observational study included patients undergoing general anesthesia over a 12-month period. Using multiple variable penalized logistic regression in a one-group before-and-after design, we compared the categorized rates of PACU MV to examine the effect of sugammadex introduction following a post-hoc chart review to ascertain the reason for postoperative MV. Additionally, multiple variable linear regression was used to assess for differences in PACU LOS and emergence time within a propensity-matched set of patients receiving neostigmine or sugammadex. RESULTS: In total, 7,217 surgical cases met the inclusion criteria: 3,798 before and 3,419 after sugammadex introduction. The incidence of PACU MV was 2.3% before and 1.8% after (P = 0.118) sugammadex introduction. PACU MV due to residual neuromuscular blockade (rNMB) decreased from 0.63% to 0.20% (P = 0.005). Ventilation because of other causes was unchanged. PACU LOS and emergence time were unchanged in the propensity-matched set of 1,444 patients. CONCLUSIONS: rNMB was an important contributor to PACU MV utilization and its incidence significantly decreased after sugammadex introduction. The selected efficiency measures may not have been sufficiently granular to identify improvements following introduction.
Objectives
This research explored the assessment of self-directed learning readiness within the comprehensive evaluation of medical students’ knowledge and skills and the extent to which several variables predicted participants’ self-directed learning readiness prior to their graduation.
Methods
Five metrics for evaluating medical students were considered in a multiple regression analysis. Fourth-year medical students at a competitive US medical school received an informed consent and an online survey. Participants voluntarily completed a self-directed learning readiness scale that assessed four subsets of self-directed learning readiness and consented to the release of their academic records.
Results
The assortment of metrics considered in this study only vaguely captured students’ self-directedness. The strongest predictors were faculty evaluations of students’ performance on clerkship rotations. Specific clerkship grades were mildly predictive of three subscales. The Pediatrics clerkship modestly predicted critical self-evaluation (r=-.30, p=.01) and the Psychiatry clerkship mildly predicted learning self-efficacy (r =-.30, p=.01), while the Junior Surgery clerkship nominally correlated with participants’ effective organization for learning (r=.21, p=.05). Other metrics examined did not contribute to predicting participants’ readiness for self-directed learning.
Conclusions
Given individual differences among participants for the variables considered, no combination of students’ grades and/or test scores overwhelmingly predicted their aptitude for self-directed learning. Considering the importance of fostering medical students’ self-directed learning skills, schools need a reliable and pragmatic approach to measure them. This data analysis, however, offered no clear-cut way of documenting students’ self-directed learning readiness based on the evaluation metrics included.
The re-establishment of conscious awareness after discontinuing general anesthesia has often been assumed to be the inverse of loss of consciousness. This is despite the obvious asymmetry in the initiation and termination of natural sleep. In order to characterize the restoration of consciousness after surgery, we recorded frontal electroencephalograph (EEG) from 100 patients in the operating room during maintenance and emergence from general anesthesia. We have defined, for the first time, 4 steady-state patterns of anesthetic maintenance based on the relative EEG power in the slow-wave (,14 Hz) frequency bands that dominate sleep and anesthesia. Unlike single-drug experiments performed in healthy volunteers, we found that surgical patients exhibited greater electroencephalographic heterogeneity while re-establishing conscious awareness after drug discontinuation. Moreover, these emergence patterns could be broadly grouped according to the duration and rapidity of transitions amongst these slow-wave dominated brain states that precede awakening. Most patients progressed gradually from a pattern characterized by strong peaks of delta (0.5-4 Hz) and alpha/spindle (8-14 Hz) power ('Slow-Wave Anesthesia') to a state marked by low delta-spindle power ('Non Slow-Wave Anesthesia') before awakening. However, 31% of patients transitioned abruptly from Slow-Wave Anesthesia to waking; they were also more likely to express pain in the post-operative period. Our results, based on sleep-staging classification, provide the first systematized nomenclature for tracking brain states under general anesthesia from maintenance to emergence, and suggest that these transitions may correlate with post-operative outcomes such as pain.
Krüppel-like factor 4 (KLF4) is a zinc-finger transcription factor with tumor suppressive activity in colorectal cancer. Here, we investigated whether KLF4 is involved in maintaining genetic stability in mouse embryonic fibroblasts (MEFs) isolated from mice wild type (+/+), heterozygous (+/−), or homozygous (−/−) for the Klf4 alleles. Compared to Klf4+/+ and Klf4+/− MEFs, Klf4−/− MEFs had both a higher level of apoptosis and rate of proliferation. Quantification of chromosome numbers showed that Klf4−/− MEFs were aneuploid. A higher number of Klf4−/− MEFs exhibited γ-H2AX foci and had higher amounts of γ-H2AX compared to controls. Cytogenetic analysis demonstrated the presence of numerous chromosome aberrations including dicentric chromosomes, chromatid breaks, and double minute chromosomes in Klf4−/− cells but in few, if any, Klf4+/+ or Klf4+/− MEFs. Approximately 25% of Klf4−/− MEFs exhibited centrosome amplification in contrast to the less than 5% of Klf4+/+ or Klf4+/− MEFs. Finally, only Klf4−/− MEFs were capable of anchorage-independent growth. Taken together, these findings demonstrate that MEFs null for the Klf4 alleles are genetically unstable, as evidenced by the presence of aneuploidy, chromosome aberration and centrosome amplification. The results support a crucial role for KLF4 in maintaining genetic stability and as a tumor suppressor.
Neurofibrillary tangles (NFTs), composed of truncated and hyperphosphorylated tau, are a common feature of numerous aging-related neurodegenerative diseases, including Alzheimer's disease (AD). However, the molecular mechanisms mediating tau truncation and aggregation during aging remain elusive. Here we show that asparagine endopeptidase (AEP), a lysosomal cysteine proteinase, is activated during aging and proteolytically degrades tau, abolishes its microtubule assembly function, induces tau aggregation and triggers neurodegeneration. AEP is upregulated and active during aging and is activated in human AD brain and tau P301S-transgenic mice with synaptic pathology and behavioral impairments, leading to tau truncation in NFTs. Tau P301S-transgenic mice with deletion of the gene encoding AEP show substantially reduced tau hyperphosphorylation, less synapse loss and rescue of impaired hippocampal synaptic function and cognitive deficits. Mice infected with adeno-associated virus encoding an uncleavable tau mutant showed attenuated pathological and behavioral defects compared to mice injected with adeno-associated virus encoding tau P301S. Together, these observations indicate that AEP acts as a crucial mediator of tau-related clinical and neuropathological changes. Inhibition of AEP may be therapeutically useful for treating tau-mediated neurodegenerative diseases.
We present the effect of the DNA damage efficiency by excitation wavelengths above 700 nm within d–d transition bands of (L-lysine) (dppz) Cu(II) complexes. Our results show significant DNA cleavage between 700 and 755 nm. The efficiency of photosensitized DNA cleavage and quantum yield of singlet oxygen production at different excitation wavelengths have been determined to gain insight into the involvement of the d–d band in the DNA damage process. Time-dependent density functional (TD-DFT) calculations were performed to understand the influence of the metal to L-lysine transition on the d–d bands of the Cu(II) complex-DNA moiety. It is found that the involvement of d–d transition in the reaction pathway of singlet oxygen formation seems to play an important role in the DNA cleavage efficiency using light of wavelength above 700 nm.