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4.  Successful use of daily intravenous infusion of C1 esterase inhibitor concentrate in the treatment of a hereditary angioedema patient with ascites, hypovolemic shock, sepsis, renal and respiratory failure 
Hereditary angioedema (HAE) is a rare autosomal dominant disease most commonly associated with defects in C1 esterase inhibitor (C1-INH). HAE manifests as recurrent episodes of edema in various body locations. Atypical symptoms, such as ascites, acute respiratory distress syndrome, and hypovolemic shock, have also been reported. Management of HAE conventionally involves the treatment of acute attacks, as well as short- and long-term prophylaxis. Since attacks can be triggered by several factors, including stress and physical trauma, prophylactic therapy is recommended for patients undergoing surgery. Human plasma-derived C1-INH (pdC1-INH) concentrate is indicated for the treatment of both acute HAE attacks and pre-procedure prevention of HAE episodes in patients undergoing medical, dental, or surgical procedures. We report the first case of a patient with HAE who experienced an abdominal attack precipitated by a retroperitoneal bleed while being converted from warfarin to heparin in preparation for surgery. Subsequently, the patient had a protracted course in hospital with other complications, which included hypovolemic shock, ascites, severe sepsis from nosocomial pneumonia, renal and respiratory failure. Despite intensive interventions, the patient remained in a critical state for months; however, after a trial of daily intravenous infusion of pdC1-INH concentrate (Berinert®, CSL Behring GmbH, Marburg, Germany), clinical status improved, particularly renal function. Therefore, pdC1-INH concentrate may be an effective treatment option to consider for critically-ill patients with HAE.
PMCID: PMC4268856  PMID: 25520740
Berinert®; Hereditary angioedema; HAE; C1 inhibitor concentrate; C1-INH; Short-term prophylaxis; Critical care
5.  Comparative analysis of metazoan chromatin organization 
Ho, Joshua W. K. | Jung, Youngsook L. | Liu, Tao | Alver, Burak H. | Lee, Soohyun | Ikegami, Kohta | Sohn, Kyung-Ah | Minoda, Aki | Tolstorukov, Michael Y. | Appert, Alex | Parker, Stephen C. J. | Gu, Tingting | Kundaje, Anshul | Riddle, Nicole C. | Bishop, Eric | Egelhofer, Thea A. | Hu, Sheng’en Shawn | Alekseyenko, Artyom A. | Rechtsteiner, Andreas | Asker, Dalal | Belsky, Jason A. | Bowman, Sarah K. | Chen, Q. Brent | Chen, Ron A-J | Day, Daniel S. | Dong, Yan | Dose, Andrea C. | Duan, Xikun | Epstein, Charles B. | Ercan, Sevinc | Feingold, Elise A. | Ferrari, Francesco | Garrigues, Jacob M. | Gehlenborg, Nils | Good, Peter J. | Haseley, Psalm | He, Daniel | Herrmann, Moritz | Hoffman, Michael M. | Jeffers, Tess E. | Kharchenko, Peter V. | Kolasinska-Zwierz, Paulina | Kotwaliwale, Chitra V. | Kumar, Nischay | Langley, Sasha A. | Larschan, Erica N. | Latorre, Isabel | Libbrecht, Maxwell W. | Lin, Xueqiu | Park, Richard | Pazin, Michael J. | Pham, Hoang N. | Plachetka, Annette | Qin, Bo | Schwartz, Yuri B. | Shoresh, Noam | Stempor, Przemyslaw | Vielle, Anne | Wang, Chengyang | Whittle, Christina M. | Xue, Huiling | Kingston, Robert E. | Kim, Ju Han | Bernstein, Bradley E. | Dernburg, Abby F. | Pirrotta, Vincenzo | Kuroda, Mitzi I. | Noble, William S. | Tullius, Thomas D. | Kellis, Manolis | MacAlpine, David M. | Strome, Susan | Elgin, Sarah C. R. | Liu, Xiaole Shirley | Lieb, Jason D. | Ahringer, Julie | Karpen, Gary H. | Park, Peter J.
Nature  2014;512(7515):449-452.
PMCID: PMC4227084  PMID: 25164756
6.  Distinct Functions of Human Cohesin-SA1 and Cohesin-SA2 in Double-Strand Break Repair 
Molecular and Cellular Biology  2014;34(4):685-698.
Cohesin is an essential multiprotein complex that mediates sister chromatid cohesion critical for proper segregation of chromosomes during cell division. Cohesin is also involved in DNA double-strand break (DSB) repair. In mammalian cells, cohesin is involved in both DSB repair and the damage checkpoint response, although the relationship between these two functions is unclear. Two cohesins differing by one subunit (SA1 or SA2) are present in somatic cells, but their functional specificities with regard to DNA repair remain enigmatic. We found that cohesin-SA2 is the main complex corecruited with the cohesin-loading factor NIPBL to DNA damage sites in an S/G2-phase-specific manner. Replacing the diverged C-terminal region of SA1 with the corresponding region of SA2 confers this activity on SA1. Depletion of SA2 but not SA1 decreased sister chromatid homologous recombination repair and affected repair pathway choice, indicating that DNA repair activity is specifically associated with cohesin recruited to damage sites. In contrast, both cohesin complexes function in the intra-S checkpoint, indicating that cell cycle-specific damage site accumulation is not a prerequisite for cohesin's intra-S checkpoint function. Our findings reveal the unique ways in which cohesin-SA1 and cohesin-SA2 participate in the DNA damage response, coordinately protecting genome integrity in human cells.
PMCID: PMC3911484  PMID: 24324008
7.  Unpriming or Strategizing?: A Critique of Sparrow and Wegner 
PLoS ONE  2014;9(2):e87512.
When asked to randomly select answer choices on easy multiple choice questions, people select more correct answers than expected by chance. Sparrow and Wegner showed that this tendency was eliminated if participants answered questions correctly before answering randomly. They argued that answering a question correctly unprimes the tendency to choose the correct answer, thereby reducing the correct response rate close to the chance level of.5. An alternative explanation, consistent with these results, is that answering questions correctly provides a baseline, which allows participants to strategize, i.e., to match and mismatch equal numbers of their purportedly random responses to the baseline response. Three studies showed that the presence of a baseline, even when unpriming is not feasible, led to lower correct response rates than those obtained in a condition in which no baseline was available. Furthermore, the presence of a baseline led to more nonrandom sequences of correct and incorrect responses. One specific sequence–alternating correct and incorrect answers–mediated the relation between the presence of a baseline and lower correct response rate. These findings suggest that strategizing, not unpriming, accounts for Sparrow and Wegner’s results.
PMCID: PMC3914830  PMID: 24505293
8.  Improving Pharmacy Staff Knowledge and Practice on Childhood Diarrhea Management in Vietnam: Are Educational Interventions Effective? 
PLoS ONE  2013;8(10):e74882.
In many developing countries, private pharmacies play an important role in providing health information and services to local communities for common health issues. The aim of this study was to ascertain medium-term impact of educational interventions on knowledge and practice of pharmacy staff regarding management of childhood diarrhea in Vietnam.
This was a pre- and post-intervention study with 32 and 44 months difference from the time of the baseline survey to the conclusion of trainings and the time of the end-line survey, respectively. Interventions included in-class training for pharmacy staff, printed materials at the pharmacy, and supportive supervision. Knowledge/reported practice and actual practice of pharmacy staff were measured before and after interventions.
After interventions, significant improvements (p<0.01) were observed for all indexes related to pharmacy staff's knowledge about childhood diarrhea; for instance, 31% and 60% of surveyed staff asked about weight of the child and accompanying symptoms of childhood diarrhea, respectively, an increase from 11% and 45% at the baseline. Oral rehydration solution (ORS) was the most frequently reported product recommended (97% to 99%), but probiotics and antidiarrheals were the products most frequently prescribed at pharmacies. Public health facilities remained the preferred choice for referrals from pharmacies, but the use of private clinics was increasing. Consultations and advice provided to caregivers also improved, but considerable gaps between knowledge and actual practice of staff in real pharmacy settings remained.
Educational interventions were effective in improving pharmacy staff knowledge and practice regarding management of childhood diarrhea. Knowledge and actual practice of staff in real pharmacy settings did not always correlate; there is need for a stronger regulatory and law enforcement system. Interventions to improve pharmacy practice in developing countries should be focused, comprehensive, and evidence-based.
PMCID: PMC3789740  PMID: 24098355
9.  Recognition of medication information from discharge summaries using ensembles of classifiers 
Extraction of clinical information such as medications or problems from clinical text is an important task of clinical natural language processing (NLP). Rule-based methods are often used in clinical NLP systems because they are easy to adapt and customize. Recently, supervised machine learning methods have proven to be effective in clinical NLP as well. However, combining different classifiers to further improve the performance of clinical entity recognition systems has not been investigated extensively. Combining classifiers into an ensemble classifier presents both challenges and opportunities to improve performance in such NLP tasks.
We investigated ensemble classifiers that used different voting strategies to combine outputs from three individual classifiers: a rule-based system, a support vector machine (SVM) based system, and a conditional random field (CRF) based system. Three voting methods were proposed and evaluated using the annotated data sets from the 2009 i2b2 NLP challenge: simple majority, local SVM-based voting, and local CRF-based voting.
Evaluation on 268 manually annotated discharge summaries from the i2b2 challenge showed that the local CRF-based voting method achieved the best F-score of 90.84% (94.11% Precision, 87.81% Recall) for 10-fold cross-validation. We then compared our systems with the first-ranked system in the challenge by using the same training and test sets. Our system based on majority voting achieved a better F-score of 89.65% (93.91% Precision, 85.76% Recall) than the previously reported F-score of 89.19% (93.78% Precision, 85.03% Recall) by the first-ranked system in the challenge.
Our experimental results using the 2009 i2b2 challenge datasets showed that ensemble classifiers that combine individual classifiers into a voting system could achieve better performance than a single classifier in recognizing medication information from clinical text. It suggests that simple strategies that can be easily implemented such as majority voting could have the potential to significantly improve clinical entity recognition.
PMCID: PMC3502425  PMID: 22564405
10.  Pyrazinoic Acid Decreases the Proton Motive Force, Respiratory ATP Synthesis Activity, and Cellular ATP Levels▿† 
Antimicrobial Agents and Chemotherapy  2011;55(11):5354-5357.
Pyrazinoic acid, the active form of the first-line antituberculosis drug pyrazinamide, decreased the proton motive force and respiratory ATP synthesis rates in subcellular mycobacterial membrane assays. Pyrazinoic acid also significantly lowered cellular ATP levels in Mycobacterium bovis BCG. These results indicate that the predominant mechanism of killing by this drug may operate by depletion of cellular ATP reserves.
PMCID: PMC3195041  PMID: 21876062
11.  Imaging of Lymph Flow in Breast Cancer Patients after Microdose Administration of a Near-Infrared Fluorophore: Feasibility Study1 
Radiology  2008;246(3):734-741.
To prospectively demonstrate the feasibility of using indocyanine green, a near-infrared (NIR) fluorophore at the minimum dose needed for noninvasive optical imaging of lymph nodes (LNs) in breast cancer patients undergoing sentinel lymph node mapping (SLNM).
Materials and Methods
Informed consent was obtained from 24 women (age range, 30–85 years) who received intradermal subcutaneous injections of 0.31–100 μg indocyanine green in the breast in this IRB-approved, HIPAA-compliant, dose escalation study to find the minimum microdose for imaging. The breast, axilla, and sternum were illuminated with NIR light and the fluorescence generated in the tissue was collected with an NIR-sensitive intensified charged-coupled device. Lymphoscintigraphy was also performed. Resected LNs were evaluated for the presence of radioactivity, blue dye accumulation, and fluorescence. The associations between the resected LNs that were fluorescent and (a) the time elapsed between NIR fluorophore administration and resection and (b) the dosage of NIR fluorophores were tested with the Spearman rank and Pearson product moment correlation tests, respectively.
Lymph imaging consistently failed with indocyanine green microdosages between 0.31 and 0.77 μg. When indocyanine green dosages were 10 μg or higher, lymph drainage pathways from the injection site to LNs were imaged in eight of nine women; lymph propulsion was observed in seven of those eight. When propulsion in the breast and axilla regions was present, the mean apparent velocities ranged from 0.08 to 0.32 cm/sec, the time elapsed between “packets” of propelled fluid varied from 14 to 92 seconds. In patients who received 10 μg of indocyanine green or more, a weak negative correlation between the fluorescence status of resected LNs and the time between NIR fluorophore administration and LN resection was found. No statistical association was found between the fluorescence status of resected LNs and the dose of NIR fluorophore.
NIR fluorescence imaging of lymph function and LNs is feasible in humans at microdoses that would be needed for future molecular imaging of cancer-positive LNs.
PMCID: PMC3166516  PMID: 18223125
12.  Integrative Analysis of the Caenorhabditis elegans Genome by the modENCODE Project 
Gerstein, Mark B. | Lu, Zhi John | Van Nostrand, Eric L. | Cheng, Chao | Arshinoff, Bradley I. | Liu, Tao | Yip, Kevin Y. | Robilotto, Rebecca | Rechtsteiner, Andreas | Ikegami, Kohta | Alves, Pedro | Chateigner, Aurelien | Perry, Marc | Morris, Mitzi | Auerbach, Raymond K. | Feng, Xin | Leng, Jing | Vielle, Anne | Niu, Wei | Rhrissorrakrai, Kahn | Agarwal, Ashish | Alexander, Roger P. | Barber, Galt | Brdlik, Cathleen M. | Brennan, Jennifer | Brouillet, Jeremy Jean | Carr, Adrian | Cheung, Ming-Sin | Clawson, Hiram | Contrino, Sergio | Dannenberg, Luke O. | Dernburg, Abby F. | Desai, Arshad | Dick, Lindsay | Dosé, Andréa C. | Du, Jiang | Egelhofer, Thea | Ercan, Sevinc | Euskirchen, Ghia | Ewing, Brent | Feingold, Elise A. | Gassmann, Reto | Good, Peter J. | Green, Phil | Gullier, Francois | Gutwein, Michelle | Guyer, Mark S. | Habegger, Lukas | Han, Ting | Henikoff, Jorja G. | Henz, Stefan R. | Hinrichs, Angie | Holster, Heather | Hyman, Tony | Iniguez, A. Leo | Janette, Judith | Jensen, Morten | Kato, Masaomi | Kent, W. James | Kephart, Ellen | Khivansara, Vishal | Khurana, Ekta | Kim, John K. | Kolasinska-Zwierz, Paulina | Lai, Eric C. | Latorre, Isabel | Leahey, Amber | Lewis, Suzanna | Lloyd, Paul | Lochovsky, Lucas | Lowdon, Rebecca F. | Lubling, Yaniv | Lyne, Rachel | MacCoss, Michael | Mackowiak, Sebastian D. | Mangone, Marco | McKay, Sheldon | Mecenas, Desirea | Merrihew, Gennifer | Miller, David M. | Muroyama, Andrew | Murray, John I. | Ooi, Siew-Loon | Pham, Hoang | Phippen, Taryn | Preston, Elicia A. | Rajewsky, Nikolaus | Rätsch, Gunnar | Rosenbaum, Heidi | Rozowsky, Joel | Rutherford, Kim | Ruzanov, Peter | Sarov, Mihail | Sasidharan, Rajkumar | Sboner, Andrea | Scheid, Paul | Segal, Eran | Shin, Hyunjin | Shou, Chong | Slack, Frank J. | Slightam, Cindie | Smith, Richard | Spencer, William C. | Stinson, E. O. | Taing, Scott | Takasaki, Teruaki | Vafeados, Dionne | Voronina, Ksenia | Wang, Guilin | Washington, Nicole L. | Whittle, Christina M. | Wu, Beijing | Yan, Koon-Kiu | Zeller, Georg | Zha, Zheng | Zhong, Mei | Zhou, Xingliang | Ahringer, Julie | Strome, Susan | Gunsalus, Kristin C. | Micklem, Gos | Liu, X. Shirley | Reinke, Valerie | Kim, Stuart K. | Hillier, LaDeana W. | Henikoff, Steven | Piano, Fabio | Snyder, Michael | Stein, Lincoln | Lieb, Jason D. | Waterston, Robert H.
Science (New York, N.Y.)  2010;330(6012):1775-1787.
We systematically generated large-scale data sets to improve genome annotation for the nematode Caenorhabditis elegans, a key model organism. These data sets include transcriptome profiling across a developmental time course, genome-wide identification of transcription factor–binding sites, and maps of chromatin organization. From this, we created more complete and accurate gene models, including alternative splice forms and candidate noncoding RNAs. We constructed hierarchical networks of transcription factor–binding and microRNA interactions and discovered chromosomal locations bound by an unusually large number of transcription factors. Different patterns of chromatin composition and histone modification were revealed between chromosome arms and centers, with similarly prominent differences between autosomes and the X chromosome. Integrating data types, we built statistical models relating chromatin, transcription factor binding, and gene expression. Overall, our analyses ascribed putative functions to most of the conserved genome.
PMCID: PMC3142569  PMID: 21177976
13.  Chlorinated dioxins and dibenzofurans in human tissues from general populations: a selective review 
Environmental Health Perspectives  1994;102(Suppl 1):159-171.
During the past decade a considerable amount of data has been generated concerning polychlorinated dibenzodioxin (PCDD) and polychlorinated dibenzofuran (PCDF) levels in humans from many geographical locations. To organize these data in a useful fashion for environmental purposes and for consideration of human toxicity, selected portions of our data are presented in a somewhat atypical fashion, by percentage contribution of individual congeners to total PCDD/Fs in human tissue, and to the total dioxin equivalents (TEq). This is done to better characterize congener contributions from environmental contamination in various geographical regions at this time and health-related levels. To present the findings in a global perspective, data from widely different locations are presented including the United States, Germany, Vietnam, the former Soviet Union, Thailand, Cambodia, China, South Africa, and Guam.
PMCID: PMC1566889  PMID: 8187705

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