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1.  Dendrimer Brain Uptake and Targeted Therapy for Brain Injury in a Large Animal Model of Hypothermic Circulatory Arrest 
ACS Nano  2014;8(3):2134-2147.
Treatment of brain injury following circulatory arrest is a challenging health issue with no viable therapeutic options. Based on studies in a clinically relevant large animal (canine) model of hypothermic circulatory arrest (HCA)-induced brain injury, neuroinflammation and excitotoxicity have been identified as key players in mediating the brain injury after HCA. Therapy with large doses of valproic acid (VPA) showed some neuroprotection but was associated with adverse side effects. For the first time in a large animal model, we explored whether systemically administered polyamidoamine (PAMAM) dendrimers could be effective in reaching target cells in the brain and deliver therapeutics. We showed that, upon systemic administration, hydroxyl-terminated PAMAM dendrimers are taken up in the brain of injured animals and selectively localize in the injured neurons and microglia in the brain. The biodistribution in other major organs was similar to that seen in small animal models. We studied systemic dendrimer–drug combination therapy with two clinically approved drugs, N-acetyl cysteine (NAC) (attenuating neuroinflammation) and valproic acid (attenuating excitotoxicity), building on positive outcomes in a rabbit model of perinatal brain injury. We prepared and characterized dendrimer-NAC (D-NAC) and dendrimer-VPA (D-VPA) conjugates in multigram quantities. A glutathione-sensitive linker to enable for fast intracellular release. In preliminary efficacy studies, combination therapy with D-NAC and D-VPA showed promise in this large animal model, producing 24 h neurological deficit score improvements comparable to high dose combination therapy with VPA and NAC, or free VPA, but at one-tenth the dose, while significantly reducing the adverse side effects. Since adverse side effects of drugs are exaggerated in HCA, the reduced side effects with dendrimer conjugates and suggestions of neuroprotection offer promise for these nanoscale drug delivery systems.
PMCID: PMC4004292  PMID: 24499315
PAMAM dendrimers; cardiac arrest; canine model; brain injury; biodistribution; combination therapies; neuroinflammation; cytotoxicity; valproic acid; N-acetylcysteine
2.  Cerebral Blood Flow Autoregulation Is Preserved After Hypothermic Circulatory Arrest 
Patients undergoing aortic surgery with hypothermic circulatory arrest (HCA) may require prolonged rewarming, a maneuver associated with impaired cerebral blood flow (CBF) autoregulation. The purpose of this study was to determine the effects of HCA on CBF autoregulation with validated method based on near-infrared spectroscopy.
Regional cerebral oxygen saturation (rScO2) was monitored in 25 patients undergoing aortic reconstructive surgery. HCA was used in 13 patients. Autoregulation was measured continuously during surgery by calculating the linear correlation coefficient between lowfrequency changes in rScO2 and mean arterial pressure (MAP), generating the variable cerebral oximetry index (COx). When CBF autoregulation is functional, COx is near zero, as CBF and MAP are not correlated, but it approaches 1 when autoregulation is impaired (i.e., CBF is pressure passive). Based on prior studies, impaired autoregulation was defined as COx > 0.3.
COx did not differ between HCA and non-HCA groups before cardiopulmonary bypass or during the cooling phase of surgery, although the lower limit of autoregulation tended to be lower in patients before HCA (p=0.053). During patient rewarming, COx was lower in the HCA group (p=0.045) and abnormal COx was less frequent ( 31% vs 75%, p=0.047) compared with the non-HCA group.
During aortic reconstructive surgery, CBF autoregulation is preserved during the cooling phase of surgery in patients undergoing HCA. Perfusion maneuvers associated with HCA may be protective against impaired autoregulation during rewarming compared with the non-HCA group.
PMCID: PMC3972490  PMID: 24446562
Aorta operations; cerebral autoregulation
3.  Large-scale biomedical concept recognition: an evaluation of current automatic annotators and their parameters 
BMC Bioinformatics  2014;15:59.
Ontological concepts are useful for many different biomedical tasks. Concepts are difficult to recognize in text due to a disconnect between what is captured in an ontology and how the concepts are expressed in text. There are many recognizers for specific ontologies, but a general approach for concept recognition is an open problem.
Three dictionary-based systems (MetaMap, NCBO Annotator, and ConceptMapper) are evaluated on eight biomedical ontologies in the Colorado Richly Annotated Full-Text (CRAFT) Corpus. Over 1,000 parameter combinations are examined, and best-performing parameters for each system-ontology pair are presented.
Baselines for concept recognition by three systems on eight biomedical ontologies are established (F-measures range from 0.14–0.83). Out of the three systems we tested, ConceptMapper is generally the best-performing system; it produces the highest F-measure of seven out of eight ontologies. Default parameters are not ideal for most systems on most ontologies; by changing parameters F-measure can be increased by up to 0.4. Not only are best performing parameters presented, but suggestions for choosing the best parameters based on ontology characteristics are presented.
PMCID: PMC4015610  PMID: 24571547
4.  The Role of Head CT Imaging in the Evaluation of Postoperative Neurologic Deficits in Cardiac Surgery Patients 
The Annals of thoracic surgery  2012;95(2):548-554.
Computed tomography(CT) scans of the head without contrast are routinely obtained to evaluate neurologic deficits after cardiac surgery(CS), but their utility is unknown. We evaluated our experience with this imaging modality to determine its value.
We retrospectively identified CS patients with postoperative neurologic deficits occurring during the first week after surgery between January 2000 and December 2012. Stroke was defined by neurologist’s determination, while a non-focal deficit(NFD) was defined by the presence of seizure, delirium, or cognitive impairment. We defined early non-contrast head CT as occurring within 7 days of surgery. Outcomes included positive findings on CT, in-hospital mortality and length of stay(LOS). Multivariate logistic regression identified predictors of positive findings on head CT.
Within the population of 11,070 postoperative patients, 451 had early non-contrast head CT scans (4%). 202(44.7%) were associated with stroke and 249(55.2%) with NFD. Among stroke patients, 40/202(20%) showed acute infarction, 17/202(8%) showed sub-acute infarction, and 5/202(2%) showed hemorrhage. Among NFD patients, 1/248(0.4%) showed acute infarction, 4/248(1.6%) sub-acute infarction, and 1/248(0.4%) hemorrhage. There was no difference in in-hospital mortality(S:42/201(21%) versus NFD:41/248(16%), p=0.2) or LOS (S:24d versus NFD:22d, p=0.5). On multivariable logistic regression, only focal deficits and aortic procedures predicted a positive finding on CT scan.
To our knowledge, this is the only modern study to review the utility of early postoperative non-contrast head CT in CS patients. With focal neurologic deficits, this imaging modality was positive for approximately one third of patients, but rarely positive for NFD. Its use in this setting has limited utility.
PMCID: PMC3602972  PMID: 23218967
Cerebral Complications; Intensive Care
5.  Contemporary Etiologies, Risk Factors, and Outcomes after Pericardiectomy 
The Annals of thoracic surgery  2012;94(2):445-451.
The leading causes of constrictive pericarditis have changed over time leading to a commensurate change in the indications and complexity of surgical pericardiectomy. We evaluated our single-center experience to define the etiologies, risk factors, and outcomes of pericardiectomy in a modern cohort.
We retrospectively reviewed our institutional database for all patients who underwent total or partial pericardiectomy. Demographic, co-morbid, operative, and outcome data were evaluated. Survival was assessed by the Kaplan-Meier method. Multivariable Cox proportional hazards regression models examined risk factors for mortality.
From 1995–2010, 98 adults underwent pericardiectomy for constrictive disease. The most common etiologies were idiopathic (n=44), postoperative (n=30), and post-radiation (n=17). Total pericardiectomy was performed in 94 cases, most commonly through a sternotomy (n=93). Thirty-three cases were redo sternotomies, 34 underwent a concomitant procedure, and 34 required cardiopulmonary bypass. Overall in-hospital, 1-year, 5-year, and 10-year survival rates were 92.9%, 82.5%, 64.3%, and 49.2%, respectively. Survival differed sharply by etiology with idiopathic, postoperative, and post-radiation 5-year survivals of 79.8%, 55.9%, and 11.0%, respectively (p<0.001). On multivariable analysis, only the need for cardiopulmonary bypass (HR: 21.2, p=0.02) was predictive of 30-day mortality while post-radiation etiology (HR: 3.19, p=0.02) and hypoalbuminemia (HR: 0.57, p=0.03) were associated with increased 10-year mortality.
Although survival varies significantly by etiology, pericardiectomy continues to be a safe operation for constrictive pericarditis. Post-radiation pericarditis and hypoalbuminemia are significant risk factors for decreased long-term survival.
PMCID: PMC3610598  PMID: 22621875
6.  A corpus of full-text journal articles is a robust evaluation tool for revealing differences in performance of biomedical natural language processing tools 
BMC Bioinformatics  2012;13:207.
We introduce the linguistic annotation of a corpus of 97 full-text biomedical publications, known as the Colorado Richly Annotated Full Text (CRAFT) corpus. We further assess the performance of existing tools for performing sentence splitting, tokenization, syntactic parsing, and named entity recognition on this corpus.
Many biomedical natural language processing systems demonstrated large differences between their previously published results and their performance on the CRAFT corpus when tested with the publicly available models or rule sets. Trainable systems differed widely with respect to their ability to build high-performing models based on this data.
The finding that some systems were able to train high-performing models based on this corpus is additional evidence, beyond high inter-annotator agreement, that the quality of the CRAFT corpus is high. The overall poor performance of various systems indicates that considerable work needs to be done to enable natural language processing systems to work well when the input is full-text journal articles. The CRAFT corpus provides a valuable resource to the biomedical natural language processing community for evaluation and training of new models for biomedical full text publications.
PMCID: PMC3483229  PMID: 22901054
7.  Alpha II-spectrin Breakdown Products Serve as Novel Markers of Brain Injury Severity in a Canine Model of Hypothermic Circulatory Arrest 
The Annals of thoracic surgery  2009;88(2):543-550.
The development of specific biomarkers to aid in diagnosis and prognosis of neuronal injury is of paramount importance in cardiac surgery. Alpha II-spectrin is a structural protein abundant in neurons of the central nervous system and cleaved into signature fragments by proteases involved in necrotic and apoptotic cell death. We measured cerebrospinal fluid (CSF) alpha II-spectrin breakdown products (αII-SBDP’s) in a canine model of hypothermic circulatory arrest (HCA) and cardiopulmonary bypass (CPB).
Canine subjects were exposed to either 1 hour of HCA (n=8, mean lowest tympanic temperature 18.0 ± 1.2 °C), or standard CPB (n=7). CSF samples were collected prior to treatment and 8 and 24 hours post-treatment. Using polyacrylamide gel electrophoresis and immunoblotting, SBDP’s were isolated and compared between groups using computer-assisted densitometric scanning. Necrotic versus apoptotic cell death was indexed by measuring calpain and caspase-3 cleaved αII-SBDP’s (SBDP 145+150 and SBDP 120, respectively).
Animals undergoing HCA demonstrated mild patterns of histological cellular injury and clinically detectable neurologic dysfunction. Calpain-produced αII-SBDP (150kDa+145kDa bands-necrosis) 8 hours post HCA, were significantly increased (p=0.02) as compared to levels prior to HCA and remained elevated at 24 hours post HCA. In contrast caspase-3 αII-SBDP (120kDa band-apoptosis) were not significantly increased. Animals receiving CPB did not demonstrate clinical or histological evidence of injury, with no increases in necrotic or apoptotic cellular markers.
We report the use of αII-SBDP’s as markers of neurological injury following cardiac surgery. Our analysis demonstrates that Calpain and Caspase produced αII-SBDP’s may be an important and novel marker of neurologic injury following HCA.
PMCID: PMC3412404  PMID: 19632410
Brain Injury; cardiac surgery; neuroprotection; hypothermic circulatory arrest; biomarkers
8.  Concept annotation in the CRAFT corpus 
BMC Bioinformatics  2012;13:161.
Manually annotated corpora are critical for the training and evaluation of automated methods to identify concepts in biomedical text.
This paper presents the concept annotations of the Colorado Richly Annotated Full-Text (CRAFT) Corpus, a collection of 97 full-length, open-access biomedical journal articles that have been annotated both semantically and syntactically to serve as a research resource for the biomedical natural-language-processing (NLP) community. CRAFT identifies all mentions of nearly all concepts from nine prominent biomedical ontologies and terminologies: the Cell Type Ontology, the Chemical Entities of Biological Interest ontology, the NCBI Taxonomy, the Protein Ontology, the Sequence Ontology, the entries of the Entrez Gene database, and the three subontologies of the Gene Ontology. The first public release includes the annotations for 67 of the 97 articles, reserving two sets of 15 articles for future text-mining competitions (after which these too will be released). Concept annotations were created based on a single set of guidelines, which has enabled us to achieve consistently high interannotator agreement.
As the initial 67-article release contains more than 560,000 tokens (and the full set more than 790,000 tokens), our corpus is among the largest gold-standard annotated biomedical corpora. Unlike most others, the journal articles that comprise the corpus are drawn from diverse biomedical disciplines and are marked up in their entirety. Additionally, with a concept-annotation count of nearly 100,000 in the 67-article subset (and more than 140,000 in the full collection), the scale of conceptual markup is also among the largest of comparable corpora. The concept annotations of the CRAFT Corpus have the potential to significantly advance biomedical text mining by providing a high-quality gold standard for NLP systems. The corpus, annotation guidelines, and other associated resources are freely available at
PMCID: PMC3476437  PMID: 22776079
9.  BioLemmatizer: a lemmatization tool for morphological processing of biomedical text 
The wide variety of morphological variants of domain-specific technical terms contributes to the complexity of performing natural language processing of the scientific literature related to molecular biology. For morphological analysis of these texts, lemmatization has been actively applied in the recent biomedical research.
In this work, we developed a domain-specific lemmatization tool, BioLemmatizer, for the morphological analysis of biomedical literature. The tool focuses on the inflectional morphology of English and is based on the general English lemmatization tool MorphAdorner. The BioLemmatizer is further tailored to the biological domain through incorporation of several published lexical resources. It retrieves lemmas based on the use of a word lexicon, and defines a set of rules that transform a word to a lemma if it is not encountered in the lexicon. An innovative aspect of the BioLemmatizer is the use of a hierarchical strategy for searching the lexicon, which enables the discovery of the correct lemma even if the input Part-of-Speech information is inaccurate. The BioLemmatizer achieves an accuracy of 97.5% in lemmatizing an evaluation set prepared from the CRAFT corpus, a collection of full-text biomedical articles, and an accuracy of 97.6% on the LLL05 corpus. The contribution of the BioLemmatizer to accuracy improvement of a practical information extraction task is further demonstrated when it is used as a component in a biomedical text mining system.
The BioLemmatizer outperforms other tools when compared with eight existing lemmatizers. The BioLemmatizer is released as an open source software and can be downloaded from
PMCID: PMC3359276  PMID: 22464129
10.  Serum Levels of Neuron-Specific UCHL1 Predict Brain Injury in a Canine Model of Hypothermic Circulatory Arrest 
Ubiquitin carboxyl-terminal esterase-L1 (UCHL1) is a protein highly selectively expressed in neurons and has been linked to neurodegenerative disease in humans. We hypothesize that UCHL1 would be an effective serum biomarker for brain injury as tested in canine models of hypothermic circulatory arrest (HCA) and cardiopulmonary bypass (CPB).
Canines were exposed to CPB (n=14), 1 hour(h) HCA (n=11), or 2h-HCA (n=20). Cerebrospinal fluid (CSF) and serum were collected at baseline, 8h, and 24h post-treatment. UCHL1 levels were measured using a sandwich enzyme-linked immunosorbent assay (ELISA). Neurological function and histopathology were scored at 24h, and UCHL1 immunoreactivity was examined at 8h.
Baseline UCHL1 protein levels in CSF and serum were similar for all groups. In serum, UCHL1 levels were elevated at 8h post-treatment for 2h-HCA subjects compared to baseline values (p<0.01), and also compared to CPB canines at 8h (p<0.01). A serum UCHL1 level above 3.9ng/(mg total protein) at 8h had the best discriminatory power for predicting functional disability. In CSF, UCHL1 was elevated in all groups at 8h post-treatment compared to baseline (p<0.01). However, UCHL1 levels in CSF remained elevated at 24h only in 2h-HCA subjects (p<0.01). Functional and histopathology scores were closely correlated (Pearson’s coefficient: 0.66; p<0.01), and were significantly worse in 2h-HCA animals.
This is the first report associating elevated serum UCHL1 with brain injury. The novel neuronal biomarker UCHL1 is increased in serum 8h after severe neurological insult in 2h-HCA animals compared with CPB animals. These results support the potential for use in cardiac surgery patients, and form the basis for clinical correlation in humans.
PMCID: PMC3177106  PMID: 21924148
Animal Model; Cardiopulmonary bypass (CPB); Biomarker; Hypothermia/circulatory arrest; Neurology/Neurologic injury
11.  Society of Thoracic Surgeons Risk Score Predicts Hospital Charges and Resource Utilization After Aortic Valve Replacement 
The impact of Society of Thoracic Surgeons (STS) predicted mortality risk score on resource utilization after aortic valve replacement (AVR) has not been previously studied.
We hypothesize that increasing STS risk scores in patients having AVR are associated with greater hospital charges.
Design, Setting, and Patients
Clinical and financial data for patients undergoing AVR at a tertiary care, university hospital over a ten-year period (1/2000–12/2009) were retrospectively reviewed. The current STS formula (v2.61) for in-hospital mortality was used for all patients. After stratification into risk quartiles (Q), index admission hospital charges were compared across risk strata with Rank-Sum tests. Linear regression and Spearman’s coefficient assessed correlation and goodness of fit. Multivariable analysis assessed relative contributions of individual variables on overall charges.
Main Outcome Measures
Inflation-adjusted index hospitalization total charges
553 patients had AVR during the study period. Average predicted mortality was 2.9% (±3.4) and actual mortality was 3.4% for AVR. Median charges were greater in the upper Q of AVR patients [Q1–3,$39,949 (IQR32,708–51,323) vs Q4,$62,301 (IQR45,952–97,103), p=<0.01]. On univariate linear regression, there was a positive correlation between STS risk score and log-transformed charges (coefficient: 0.06, 95%CI 0.05–0.07, p<0.01). Spearman’s correlation R-value was 0.51. This positive correlation persisted in risk-adjusted multivariable linear regression. Each 1% increase in STS risk score was associated with an added $3,000 in hospital charges.
This study showed increasing STS risk score predicts greater charges after AVR. As competing therapies such as percutaneous valve replacement emerge to treat high risk patients, these results serve as a benchmark to compare resource utilization.
PMCID: PMC3156832  PMID: 21497834
Aortic Valve Replacement; Resource Utilization; Society of Thoracic Surgeons Risk Score
12.  Low Potassium Dextran is Superior to University of Wisconsin Solution in High Risk Lung Transplant Recipients 
The ideal solution for recovery of donor lungs remains unknown. Low potassium dextran (LPD) solution is most common, but University of Wisconsin (UW) solution is also used. The United Network for Organ Sharing (UNOS) database allows assessment of preservation solutions in a large cohort of lung transplant (LTx) patients.
We retrospectively reviewed the UNOS dataset for adult primary LTx patients (2005–2008) whose donor lungs were recovered with UW or LPD solution. Patients were stratified by UW vs. LPD, and secondarily grouped by quartiles of the lung allocation score (LAS) to examine high risk recipients. Kaplan-Meier (KM) short term mortality (30d, 90d, 1 yr), and rejection in the 1st yr, were examined for intervals with adequate follow-up. Cox proportional hazard regression using 11 variables examined all cause 1-yr mortality.
Of 4455 patients, 4161 (93.4%) received LPD lungs and 294 (6.6%) received UW lungs. 1105 (24.8%) patients died during the study. There was no mortality difference based on flush solution with all patients examined together. However, patients in the upper two LAS quartiles (Q3:37.8-45.4, Q4:>45.4) receiving LPD lungs had greater 1 yr survival (81.5% vs.73.5%, p=0.02). On multivariable analysis, flush with UW solution resulted in an increased risk of 1 yr mortality (Hz ratio 1.77[1.21–2.58], p=0.003) compared to LPD. Preservation solution did not affect rejection rates in the year after LTx. KM modeling demonstrated the impact of flush solution on survival (p=0.02).
This study is the largest modern cohort to evaluate the effect of donor lung flush solutions on survival in adult LTx. UW solution increases the risk of 1 yr mortality in high risk LTx recipients.
PMCID: PMC3132206  PMID: 20634098
Lung Transplantation; UNOS; organ preservation
13.  The Impact of the Lung Allocation Score on Resource Utilization After Lung Transplantation in the United States 
The United States lung allocation score (LAS) allows rapid organ allocation to higher acuity patients. Although, waitlist time and waitlist mortality have improved, the costs of lung transplantation (LTx) in these higher acuity patients are largely unknown. We hypothesize that LTx in high LAS recipients is associated with increased charges and resource utilization.
Methods and Materials
Clinical and financial data for LTx patients at our institution in the post-LAS era (5/2005–2009) were reviewed with follow-up through 12/2009. Patients were stratified by LAS quartiles (Q). Total hospital charges for index admission and all admissions within 1yr of LTx were compared between Q4 versus the Q1–3 using Rank-Sum and Kruskal-Wallis tests, as charge data were not normally distributed.
84 LTx’s were performed during the study period. 63 (75%) survived 1yr; 10 (11.9%) died during the index admission. Median LAS was 37.5 (interquartile range (IQR) 34.3–44.8). LAS quartiles were: Q1,30.1–34.3, n=21; Q2,34.4–37.5, n=21; Q3,37.6–44.8, n=21; Q4,44.9–94.3, n=21. Charges for index admission were: Q4,$276,668 (IQR191,301–300,156) vs. Q1–3, $153,995(IQR 129,796–176,849), P<0.001. Index admission median length of stay was greater in Q4 (Q4:35d IQR 23–46 vs Q1–3:15d IQR11–22, P=0.003). For 1yr charges: Q4, $292,247 (IQR 229,192–421,597) vs. Q1–3, $188,342 (IQR 153,455–252,045), P=0.002. Index admission and 1yr charges in Q4 were higher than other quartiles when examined individually.
This is the first study to show increased charges in high LAS patients. Charges for the index admission and hospital care in the year post-LTx were higher in the highest LAS quartile compared to patients in the lowest 75% of LAS.
PMCID: PMC3132211  PMID: 20869886
Lung Transplantation; Resource Utilization
14.  Glutamate Excitotoxicity Mediates Neuronal Apoptosis After Hypothermic Circulatory Arrest 
The Annals of thoracic surgery  2010;89(2):440-445.
Prolonged hypothermic circulatory arrest results in neuronal cell death and neurologic injury. We have previously shown that hypothermic circulatory arrest causes both neuronal apoptosis and necrosis in a canine model. Inhibition of neuronal nitric oxide synthase reduced neuronal apoptosis, while glutamate receptor antagonism reduced necrosis in our model. This study was undertaken to determine whether glutamate receptor antagonism reduces nitric oxide formation and neuronal apoptosis after hypothermic circulatory arrest.
Sixteen hound dogs underwent 2 hours of circulatory arrest at 18°C and were sacrificed after 8 hours. Group 1 (n=8) was treated with MK-801, 0.75 mg/kg IV prior to arrest followed by 75 μg/kg/hr infusion. Group 2 dogs (n=8) received vehicle only. Intracerebral levels of excitatory amino acids and citrulline, an equal co-product of nitric oxide, were measured. Apoptosis, identified by H&E staining and confirmed by electron microscopy, was blindly scored from 0 (normal) to 100 (severe injury), while nick-end labeling demonstrated DNA fragmentation.
Group 1 and 2 dogs had similar intracerebral levels of glutamate. However, MK-801 significantly reduced intracerebral glycine and citrulline levels as compared to HCA controls. MK-801 significantly inhibited apoptosis (7.92 ± 7.85 vs. 62.08 ± 6.28, Group 1 vs. 2, p<0.001).
Our results showed that glutamate receptor antagonism significantly reduced nitric oxide formation and neuronal apoptosis. We provide evidence that glutamate excitotoxicity mediates neuronal apoptosis in addition to necrosis after hypothermic circulatory arrest. Clinical glutamate receptor antagonists may have therapeutic benefit in ameliorating both types of neurologic injury after hypothermic circulatory arrest.
PMCID: PMC3076934  PMID: 20103318
Animal Model; Apoptosis; Brain; Hypothermic Circulatory Arrest; Nitric Oxide
Behavioural neurology  2010;22(1-2):63-71.
Background and Purpose
Impaired cardiac function can adversely affect the brain via decreased perfusion. The purpose of this study was to determine if cardiac ejection fraction (EF) is associated with cognitive performance, and whether this is modified by low blood pressure.
Neuropsychological testing evaluating multiple cognitive domains, measurement of mean arterial pressure (MAP), and measurement of EF were performed in 234 individuals with coronary artery disease. The association between level of EF and performance within each cognitive domain was explored, as was the interaction between low MAP and EF.
Adjusted global cognitive performance, as well as performance in visuoconstruction and motor speed, was significantly directly associated with cardiac EF. This relationship was not entirely linear, with a steeper association between EF and cognition at lower levels of EF than at higher levels. Patients with low EF and low MAP at the time of testing had worse cognitive performance than either of these alone, particularly for the global and motor speed cognitive scores.
Low EF may be associated with worse cognitive performance, particularly among individuals with low MAP and for cognitive domains typically associated with vascular cognitive impairment. Further care should be paid to hypotension in the setting of heart failure, as this may exacerbate cerebral hypoperfusion.
PMCID: PMC3065346  PMID: 20543460
Heart failure; Cognition; Blood pressure; Brain ischemia
16.  Transcriptional Profile of Brain Injury in Hypothermic Circulatory Arrest and Cardiopulmonary Bypass 
The Annals of thoracic surgery  2010;89(6):1965-1971.
Little is known about the molecular mechanisms of neurologic complications after hypothermic circulatory arrest (HCA) with cardiopulmonary bypass (CPB). Canine genome sequencing allows profiling of genomic changes after HCA and CPB alone. We hypothesize that gene regulation will increase with increased severity of injury.
Dogs underwent 2-hour HCA at 18°C (n = 10), 1-hour HCA (n = 8), or 2-hour CPB at 32°C alone (n = 8). In each group, half were sacrificed at 8 hours and half at 24 hours after treatment. After neurologic scoring, brains were harvested for genomic analysis. Hippocampal RNA isolates were analyzed using canine oligonucleotide expression arrays containing 42,028 probes.
Consistent with prior work, dogs that underwent 2-hour HCA experienced severe neurologic injury. One hour of HCA caused intermediate clinical damage. Cardiopulmonary bypass alone yielded normal clinical scores. Cardiopulmonary bypass, 1-hour HCA, and 2-hour HCA groups historically demonstrated increasing degrees of histopathologic damage (previously published). Exploratory analysis revealed differences in significantly regulated genes (false discovery rate < 10%, absolute fold change ≥ 1.2), with increases in differential gene expression with injury severity. At 8 hours and 24 hours after insult, 2-hour HCA dogs had 502 and 1,057 genes regulated, respectively; 1-hour HCA dogs had 179 and 56 genes regulated; and CPB alone dogs had 5 and 0 genes regulated.
Our genomic profile of canine brains after HCA and CPB revealed 1-hour and 2-hour HCA induced markedly increased gene regulation, in contrast to the minimal effect of CPB alone. This adds to the body of neurologic literature supporting the safety of CPB alone and the minimal effect of CPB on a normal brain, while illuminating genomic results of both.
PMCID: PMC3031914  PMID: 20494057
17.  Exploring species-based strategies for gene normalization 
We introduce a system developed for the BioCreativeII.5 community evaluation of information extraction of proteins and protein interactions. The paper focuses primarily on the gene normalization task of recognizing protein mentions in text and mapping them to the appropriate database identifiers based on contextual clues. We outline a “fuzzy” dictionary lookup approach to protein mention detection that matches regularized text to similarly-regularized dictionary entries. We describe several different strategies for gene normalization that focus on species or organism mentions in the text, both globally throughout the document and locally in the immediate vicinity of a protein mention, and present the results of experimentation with a series of system variations that explore the effectiveness of the various normalization strategies, as well as the role of external knowledge sources. While our system was neither the best nor the worst performing system in the evaluation, the gene normalization strategies show promise and the system affords the opportunity to explore some of the variables affecting performance on the BCII.5 tasks.
PMCID: PMC2929766  PMID: 20671318
biomedical natural language processing; information extraction; gene normalization; text mining
18.  Do management strategies for coronary artery disease influence 6 year cognitive outcomes? 
The Annals of thoracic surgery  2009;88(2):445-454.
Previous uncontrolled studies have suggested that there is late cognitive decline after coronary artery bypass grafting that may be attributable to use of the cardiopulmonary bypass pump.
In this prospective, nonrandomized, longitudinal study, we compared cognitive outcomes after on-pump coronary artery bypass surgery (n=152) with: off-pump bypass surgery (n=75); nonsurgical cardiac comparison subjects (n=99); and 69 heart-healthy comparison (HHC) subjects. The primary outcome measure was change from baseline to 72 months in the following cognitive domains: Verbal memory, Visual memory, Visuoconstruction, Language, Motor speed, Psychomotor speed, Attention, Executive function, and a composite Global score.
There were no consistent differences in 72-month cognitive outcomes among the 3 groups with coronary artery disease (CAD). The CAD groups had lower baseline performance, and a greater degree of decline compared to HHC. The degree of change was small with none of the groups having > 0.5 SD decline. None of the groups were substantially worse at 72 months compared to baseline.
Compared to subjects with no vascular disease risk factors, the CAD patients had lower baseline cognitive performance and greater degrees of decline over 72 months, suggesting that in these patients, vascular disease may have an impact on cognitive performance. We found no significant differences in the long-term cognitive outcomes among patients with various CAD therapies, indicating that management strategy for CAD is not an important determinant of long-term cognitive outcomes.
PMCID: PMC2753795  PMID: 19632391
Neurocognitive deficits; Outcomes; CABG; vascular disease
19.  A UIMA wrapper for the NCBO annotator 
Bioinformatics  2010;26(14):1800-1801.
Summary: The Unstructured Information Management Architecture (UIMA) framework and web services are emerging as useful tools for integrating biomedical text mining tools. This note describes our work, which wraps the National Center for Biomedical Ontology (NCBO) Annotator—an ontology-based annotation service—to make it available as a component in UIMA workflows.
Availability: This wrapper is freely available on the web at as part of the UIMA tools distribution from the Center for Computational Pharmacology (CCP) at the University of Colorado School of Medicine. It has been implemented in Java for support on Mac OS X, Linux and MS Windows.
PMCID: PMC2894505  PMID: 20505005
20.  Subjective memory symptoms in surgical and nonsurgical coronary artery patients: 6-Year follow-up 
The Annals of thoracic surgery  2009;87(1):27-34.
Self-reported cognitive and memory complaints following coronary artery bypass graft surgery (CABG) are common. Several studies have attempted to quantify the incidence of such complaints and to examine the relationship between subjective and objective cognitive functioning, but the etiology and longitudinal course of these self-reports remain unclear.
Measures of subjective memory complaints were compared in two groups: 220 CABG patients and 92 nonsurgical cardiac comparisons at 3 months, and 1, 3, and 6 years. At 6 years, additional measures were used to quantify memory self-assessment. The frequency of subjective complaints at each time point was determined and associations with objective cognitive performance as well as depression were examined.
At early (3-month and/or 1-year) follow-up, subjective memory complaints were reported more often by the CABG than the nonsurgical group (45.5% vs. 17.0%, p<0.0001). By 6 years, the frequency of complaints was similar (52%) in both groups. Subjective memory ratings were significantly correlated with performance on several memory tests at 6 years. This relationship was not confounded by depression.
Subjective memory complaints are more frequent early in follow-up in patients undergoing CABG than in controls, but by 6 years they are similar. The increase in subjective complaints over time may be related to progression of underlying cerebrovascular disease. Unlike previous studies, we found that subjective memory assessments were correlated with objective performance on several memory tests. Although subjective memory complaints are more common in patients with depression, they cannot be explained by depression alone.
PMCID: PMC2753233  PMID: 19101263
CABG; neurocognitive deficits; outcomes; brain
21.  U-Compare: share and compare text mining tools with UIMA 
Bioinformatics  2009;25(15):1997-1998.
Summary: Due to the increasing number of text mining resources (tools and corpora) available to biologists, interoperability issues between these resources are becoming significant obstacles to using them effectively. UIMA, the Unstructured Information Management Architecture, is an open framework designed to aid in the construction of more interoperable tools. U-Compare is built on top of the UIMA framework, and provides both a concrete framework for out-of-the-box text mining and a sophisticated evaluation platform allowing users to run specific tools on any target text, generating both detailed statistics and instance-based visualizations of outputs. U-Compare is a joint project, providing the world's largest, and still growing, collection of UIMA-compatible resources. These resources, originally developed by different groups for a variety of domains, include many famous tools and corpora. U-Compare can be launched straight from the web, without needing to be manually installed. All U-Compare components are provided ready-to-use and can be combined easily via a drag-and-drop interface without any programming. External UIMA components can also simply be mixed with U-Compare components, without distinguishing between locally and remotely deployed resources.
PMCID: PMC2712335  PMID: 19414535
22.  Biomedical Discovery Acceleration, with Applications to Craniofacial Development 
PLoS Computational Biology  2009;5(3):e1000215.
The profusion of high-throughput instruments and the explosion of new results in the scientific literature, particularly in molecular biomedicine, is both a blessing and a curse to the bench researcher. Even knowledgeable and experienced scientists can benefit from computational tools that help navigate this vast and rapidly evolving terrain. In this paper, we describe a novel computational approach to this challenge, a knowledge-based system that combines reading, reasoning, and reporting methods to facilitate analysis of experimental data. Reading methods extract information from external resources, either by parsing structured data or using biomedical language processing to extract information from unstructured data, and track knowledge provenance. Reasoning methods enrich the knowledge that results from reading by, for example, noting two genes that are annotated to the same ontology term or database entry. Reasoning is also used to combine all sources into a knowledge network that represents the integration of all sorts of relationships between a pair of genes, and to calculate a combined reliability score. Reporting methods combine the knowledge network with a congruent network constructed from experimental data and visualize the combined network in a tool that facilitates the knowledge-based analysis of that data. An implementation of this approach, called the Hanalyzer, is demonstrated on a large-scale gene expression array dataset relevant to craniofacial development. The use of the tool was critical in the creation of hypotheses regarding the roles of four genes never previously characterized as involved in craniofacial development; each of these hypotheses was validated by further experimental work.
Author Summary
Recent technology has made it possible to do experiments that show hundreds or even thousands of genes that play a role in a disease or other biological phenomena. Interpreting these experimental results in the light of everything that has ever been published about any of those genes is often overwhelming, and the failure to take advantage of all prior knowledge may impede biomedical research. The computer program described in this paper “reads” the biomedical literature and molecular biology databases, “reasons” about what all that information means to this experiment, and “reports” on its findings in a way that makes digesting all of this information far more efficient than ever before possible. Analysis of a large, complex dataset with this tool led rapidly to the creation of a novel hypothesis about the role of several genes in the development of the tongue, which was then confirmed experimentally.
PMCID: PMC2653649  PMID: 19325874
23.  Concept recognition for extracting protein interaction relations from biomedical text 
Genome Biology  2008;9(Suppl 2):S9.
Reliable information extraction applications have been a long sought goal of the biomedical text mining community, a goal that if reached would provide valuable tools to benchside biologists in their increasingly difficult task of assimilating the knowledge contained in the biomedical literature. We present an integrated approach to concept recognition in biomedical text. Concept recognition provides key information that has been largely missing from previous biomedical information extraction efforts, namely direct links to well defined knowledge resources that explicitly cement the concept's semantics. The BioCreative II tasks discussed in this special issue have provided a unique opportunity to demonstrate the effectiveness of concept recognition in the field of biomedical language processing.
Through the modular construction of a protein interaction relation extraction system, we present several use cases of concept recognition in biomedical text, and relate these use cases to potential uses by the benchside biologist.
Current information extraction technologies are approaching performance standards at which concept recognition can begin to deliver high quality data to the benchside biologist. Our system is available as part of the BioCreative Meta-Server project and on the internet .
PMCID: PMC2559993  PMID: 18834500
24.  Introducing meta-services for biomedical information extraction 
Genome Biology  2008;9(Suppl 2):S6.
We introduce the first meta-service for information extraction in molecular biology, the BioCreative MetaServer (BCMS; ). This prototype platform is a joint effort of 13 research groups and provides automatically generated annotations for PubMed/Medline abstracts. Annotation types cover gene names, gene IDs, species, and protein-protein interactions. The annotations are distributed by the meta-server in both human and machine readable formats (HTML/XML). This service is intended to be used by biomedical researchers and database annotators, and in biomedical language processing. The platform allows direct comparison, unified access, and result aggregation of the annotations.
PMCID: PMC2559990  PMID: 18834497
25.  Overview of BioCreative II gene mention recognition 
Genome Biology  2008;9(Suppl 2):S2.
Nineteen teams presented results for the Gene Mention Task at the BioCreative II Workshop. In this task participants designed systems to identify substrings in sentences corresponding to gene name mentions. A variety of different methods were used and the results varied with a highest achieved F1 score of 0.8721. Here we present brief descriptions of all the methods used and a statistical analysis of the results. We also demonstrate that, by combining the results from all submissions, an F score of 0.9066 is feasible, and furthermore that the best result makes use of the lowest scoring submissions.
PMCID: PMC2559986  PMID: 18834493

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