Roohk HV,Zaidi AR
Department of Surgery, University of California Irvine , Irvine, California.
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A review of glycated albumin as an intermediate glycation index for controlling diabetes.
J Diabetes Sci Technol. 2008 Nov;2(6):1114-21
INTRODUCTION: This article reviews glycated albumin (GA) as a potential intermediate-term glycation index to fill the gap between self-monitoring of blood glucose (SMBG) and hemoglobin A1c testing in diabetes management. The introduction gives an assessment of available short-, medium-, and long-term glycemic indicators. METHODOLOGIES AND UTILITY: Methods of GA measurement are summarized, and the variance of normal and diabetic GA values are discussed. Greatest uniformity in GA measurement is generally associated with immunoassay and the newer affinity chromatography methodologies utilized by reference laboratories. Utility of GA measurement includes its value as a marker for glycation, its substantial relationship to diabetes complications such as nephropathy and coronary artery disease, and as an unambiguous indicator of glycemic control in diabetes patients undergoing hemodialysis. Studies support the utility of GA in detecting short-term changes in glycemic control, and GA testing has been strongly recommended for gestational diabetes. RESULTS AND DISCUSSION: The results of a survey with mailings to over 3500 diabetes care professionals primarily in the United States are outlined and analyzed (margin of error: +/-6.5%, 95% confidence). Respondents strongly supported the need for a test for intermediate glycemic control as well as the utility of a rapid GA test as a monthly glycemic indicator. CONCLUSIONS: Such a test, as yet unavailable, could increase compliance and enhance empowerment among diabetes patients. It also has the potential to reduce the number of recommended SMBG tests, which may result in significant health care cost savings.
PMID: 19885300
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Chanan G
Department of Physics and Astronomy, University of California, Irvine, California 92697, USA. gchanan@galaxy.ps.uci.edu
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Limitations on the control of hexagonal mirror segment figures by means of edge measurements.
Appl Opt. 2009 Nov 1;48(31):6074-81
Giant segmented telescopes in general require in situ control of the figures of their hexagonal segments. The necessary inputs may be either direct, through surface measurements, or indirect, through measurements of the intersegment edge heights. We investigate the limitations on the indirect (edge height) control that follow from the geometrical properties of hexagonal surfaces and find that these may be substantial. In particular, there are many unmeasurable modes, which we construct and count systematically, and whose potential effect on the segment figure problem we discuss.
PMID: 19881675
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Wodarz D,Levy DN
Department of Ecology and Evolutionary Biology and Department of Mathematics, 321 Steinhaus Hall, University of California, Irvine, California 92697, USA. dwodarz@uci.edu
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Multiple HIV-1 infection of cells and the evolutionary dynamics of cytotoxic T lymphocyte escape mutants.
Evolution. 2009 Sep;63(9):2326-39
Cytotoxic T lymphocytes (CTL) are an important branch of the immune system, killing virus-infected cells. Many viruses can mutate so that infected cells are not killed by CTL anymore. This escape can contribute to virus persistence and disease. A prominent example is HIV-1. The evolutionary dynamics of CTL escape mutants in vivo have been studied experimentally and mathematically, assuming that a cell can only be infected with one HIV particle at a time. However, according to data, multiple virus particles frequently infect the same cell, a process called coinfection. Here, we study the evolutionary dynamics of CTL escape mutants in the context of coinfection. A mathematical model suggests that an intermediate strength of the CTL response against the wild-type is most detrimental for an escape mutant, minimizing overall virus load and even leading to its extinction. A weaker or, paradoxically, stronger CTL response against the wild-type both lead to the persistence of the escape mutant and higher virus load. It is hypothesized that an intermediate strength of the CTL response, and thus the suboptimal virus suppression observed in HIV-1 infection, might be adaptive to minimize the impact of existing CTL escape mutants on overall virus load.
PMID: 19486149
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King AR,Dotsey EY,Lodola A,Jung KM,Ghomian A,Qiu Y,Fu J,Mor M,Piomelli D
Department of Pharmacology, University of California Irvine, Irvine, CA 92697, USA.
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Discovery of potent and reversible monoacylglycerol lipase inhibitors.
Chem Biol. 2009 Oct 30;16(10):1045-52
Monoacylglycerol lipase (MGL) is a serine hydrolase involved in the biological deactivation of the endocannabinoid 2-arachidonoyl-sn-glycerol (2-AG). Previous efforts to design MGL inhibitors have focused on chemical scaffolds that irreversibly block the activity of this enzyme. Here, we describe two naturally occurring terpenoids, pristimerin and euphol, which inhibit MGL activity with high potency (median effective concentration, IC(50) = 93 nM and 315 nM, respectively) through a reversible mechanism. Mutational and modeling studies suggest that the two agents occupy a common hydrophobic pocket located within the putative lid domain of MGL, and each reversibly interacts with one of two adjacent cysteine residues (Cys(201) and Cys(208)) flanking such pocket. This previously unrecognized regulatory region might offer a molecular target for potent and reversible inhibitors of MGL.
PMID: 19875078
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Chen C,Xue G,Mei L,Chen C,Dong Q
Department of Psychology and Social Behavior, University of California, Irvine, CA, USA. cschen@uci.edu
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Cultural neurolinguistics.
Prog Brain Res. 2009;178:159-71
As the only species that evolved to possess a language faculty, humans have been surprisingly generative in creating a diverse array of language systems. These systems vary in phonology, morphology, syntax, and written forms. Before the advent of modern brain-imaging techniques, little was known about how differences across languages are reflected in the brain. This chapter aims to provide an overview of an emerging area of research - cultural neurolinguistics - that examines systematic cross-cultural/crosslinguistic variations in the neural networks of languages. We first briefly describe general brain networks for written and spoken languages. We then discuss language-specific brain regions by highlighting differences in neural bases of different scripts (logographic vs. alphabetic scripts), orthographies (transparent vs. nontransparent orthographies), and tonality (tonal vs. atonal languages). We also discuss neural basis of second language and the role of native language experience in second-language acquisition. In the last section, we outline a general model that integrates culture and neural bases of language and discuss future directions of research in this area.
PMID: 19874968
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Vilberg KL,Rugg MD
Department of Neurobiology and Behavior, Center for the Neurobiology of Learning and Memory, University of California, Irvine, California 92697-3800, USA. kvilberg@uci.edu
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Left parietal cortex is modulated by amount of recollected verbal information.
Neuroreport. 2009 Sep 23;20(14):1295-9
In two earlier experiments, we reported that left parietal cortex activity covaried with the amount of pictorial information recollected. The present experiment addressed the question whether our earlier results would generalize to verbal materials. Participants studied a series of word pairs and were then tested on individual old and new words in a modified remember/know task. In this task, participants were required to indicate whether recollection was accompanied by retrieval of study pairmates or not. As before, we operationally defined 'amount recollected' as the contrast between these two types of remember response. We found that the same left parietal region previously identified as sensitive to amount of recollected pictorial information is also sensitive to amount of recollected verbal information.
PMID: 19668014
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Suchard J,Nizkorodov S,Wilkinson S
Department of Emergency Medicine, University of California, Irvine Medical Center, Orange, CA, USA. jsuchard@uci.edu
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1,4-Butanediol content of aqua dots children's craft toy beads.
J Med Toxicol. 2009 Sep;5(3):120-4
INTRODUCTION: The U.S. Consumer Product Safety Commission announced a recall of Aqua Dots (Spin Master Ltd.; Toronto, Canada) on November 7, 2007 due to children becoming ill after swallowing beads from these toy craft kits. Reports suggested that the beads contained 1,4-butanediol (1,4-BD), a precursor to gamma-hydroxybutyrate (GHB), rather than the intended, but more expensive 1,5-pentanediol (1,5-PD). We measured the 1,4-BD and 1,5-PD content of Aqua Dots beads to determine if 1,5-PD had been completely substituted with 1,4-BD by the manufacturer, and if the reported clinical effects from swallowing Aqua Dots beads were consistent with the estimated ingested 1,4-BD dose. METHODS: In vitro bench research using gas chromatography-mass spectroscopy (GC-MS) was performed. Dilute samples of pure 1,4-BD and 1,5-PD in water were used for the calibration of the GC-MS instrument. We then soaked Aqua Dots beads in water for varying durations, and the resultant solutions were analyzed for 1,4-BD and 1,5-PD content. RESULTS: Aqua Dots beads weighed 79.3 mg each (+/- 0.6 mg, SD), and contained 13.7% (+/- 2.4%, SD) 1,4-BD by weight; this corresponds to a 1,4-BD content of 10.8 mg (+/- 1.9 mg, SD) per bead. No 1,5-PD was detected in any beads. CONCLUSIONS: Aqua Dots beads contained a surprisingly high amount (nearly 14%) of extractable 1,4-BD. No 1,5-PD was detected, corroborating reports that this chemical had been completely replaced with a substitute that is metabolized into GHB after ingestion. Reports of ataxia, vomiting, seizure activity, and self-limited coma in children are consistent with the ingestion of several dozen Aqua Dots beads.
PMID: 19655283
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Muftuler LT,Chen G,Hamamura MJ,Ha SH
Tu & Yuen Center for Functional Onco-Imaging, University of California, Irvine, Irvine, CA 92697-5020, USA. tugan.muftuler@uci.edu
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MREIT with SENSE acceleration using a dedicated RF coil design.
Physiol Meas. 2009 Sep;30(9):913-29
We have adapted a SENSE-accelerated imaging technique to magnetic resonance electrical impedance tomography (MREIT) in order to acquire data faster or improve spatial resolution without increasing the data acquisition time. We also designed and optimized an eight-channel, dedicated phased array coil for this application. The RF coil was designed as two planar arrays so that the open sides could accommodate the MREIT electrodes. A quasi-intrinsic decoupling scheme was used to minimize couplings between coil elements, and a restricted geometry optimization was applied to achieve high and uniform SNR within a given coil geometry and animal size. The impact of variability in the size of animals was also investigated in the optimization. This coil geometry provided approximately three times higher SNR at the center of a phantom when compared to a transmit/receive birdcage coil designed for MREIT of small animals. Therefore, the SNR was superior to the data acquired with volume coils even with three times SENSE acceleration. Both magnitude images and MREIT data were acquired from phantoms with and without SENSE acceleration, and the results were compared. The phantom studies demonstrated that conductivity maps can be reconstructed from MREIT data acquired with three times SENSE acceleration and that no discernible artifacts were observed when accelerated data acquisition was compared to non-accelerated data.
PMID: 19641236
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Chentoufi AA,Nesburn AB,Benmohamed L
Laboratory of Cellular and Molecular Immunology, The Gavin S. Herbert Eye Institute, University of California Irvine, School of Medicine, Irvine, CA, USA, aalamich@uci.edu.
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Recent advances in multivalent self adjuvanting glycolipopeptide vaccine strategies against breast cancer.
Arch Immunol Ther Exp (Warsz). 2009 Oct 29;:
Breast cancer (BrCa) is the second leading cause of cancer-related deaths for women worldwide. Evidence from both patients and mouse cancer models suggests that the simultaneous induction of BrCa-specific CD4(+) T cells, CD8(+) cytotoxic T cells, and antibodies is crucial for providing immune resistance. However, almost all current vaccines address only a single arm of the immune system, which may explain their lack of efficacy. We believe that the correct response to monovalent vaccines' "failure" is to increase our knowledge about antitumor protective immunity and to develop a multivalent vaccine molecule that can simultaneously induce multiple arms of the immune system. We highlight here recent advances in anti-BrCa peptide-based vaccine strategies with an emphasis on the self adjuvanting multivalent glycolipopeptide vaccine strategy recently developed in our laboratory and which showed promising results in both immunotherapeutic and immunoprophylactic settings.
PMID: 19866342
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Zoccola PM,Dickerson SS,Lam S
Department of Psychology and Social Behavior, 3340 Social Ecology II, University of California, Irvine, Irvine, CA 92697-7085, USA. p.m.zoccola@uci.edu
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Rumination predicts longer sleep onset latency after an acute psychosocial stressor.
Psychosom Med. 2009 Sep;71(7):771-5
OBJECTIVES: Rumination has been linked to self-reported sleep quality. However, whether rumination is related to an objective sleep parameter has not been tested. This study examined whether rumination predicts sleep onset latency (SOL) on the night after an acute psychosocial stressor. We hypothesized that those who ruminate (assessed with both trait and stressor-specific measures) would have longer SOL (assessed with objective and subjective methods). METHODS: Seventy participants delivered a 5-minute speech in front of an evaluative panel during an afternoon laboratory session. Trait rumination was assessed before the stressor. Stressor-specific rumination was captured with the frequency of task-related thoughts participants experienced during a 10-minute rest period after the stressor. Participants wore actigraphs on their wrists on the night after the laboratory session to measure objective sleep onset latency (SOL-O). Subjective sleep onset latency was estimated by participants on the subsequent morning. RESULTS: Consistent with hypotheses, trait and stressor-specific rumination predicted longer SOL-O and subjective sleep onset latency, respectively. In addition, trait and stressor-specific rumination interacted to predict longer SOL-O. SOL-O was longest among those who engaged in more stressor-specific rumination and had greater trait rumination scores. Neither rumination measure was related to sleep duration or wakefulness after sleep onset. CONCLUSIONS: The findings from this study are consistent with previous research linking rumination to subjective sleep quality. The results also suggest that post-stressor ruminative thought may predict delayed sleep onset for those with a propensity for rumination.
PMID: 19622710
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Hameed AB,Chan K,Ghamsary M,Elkayam U
Department of Obstetrics and Gynecology, Division of Maternal Fetal Medicine, University of California, Irvine, California, USA. ahameed@uci.edu
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Longitudinal changes in the B-type natriuretic peptide levels in normal pregnancy and postpartum.
Clin Cardiol. 2009 Aug;32(8):E60-2
Normal levels of B-type natriuretic peptide (BNP) are not well established in pregnancy. We obtained longitudinal BNP levels in 29 healthy pregnant women in each trimester and postpartum period, and compared these levels to the 25 nonpregnant controls. There were no significant differences among the cases and controls with respect to weight, diastolic blood pressure, and ethnicity. A total of 116 BNP values were obtained during pregnancy. The median (and range) BNP level during pregnancy was 19 (10-143) pg/ml versus 10 (10-37) pg/ml in the nonpregnant controls (p = 0.003). However, there were no statistically significant differences in the median BNP levels at various stages of pregnancy: first trimester 20 (10-115) pg/ml versus the second trimester 18 (10-112) pg/ml (p = 0.8), second trimester 18 pg/ml versus third trimester 26 (10-143) pg/ml (p = 0.06), and third trimester 26 pg/ml versus postpartum18 (10-62) pg/ml (p = 0.08). There were no significant differences between the BNP levels throughout the trimesters and postpartum period. Pregnant BNP levels were approximately twice as high as the nonpregnant BNP levels. Our study is unique in evaluating longitudinal changes in BNP levels in normal pregnancies and the postpartum period in comparison with healthy, nonpregnant controls. It demonstrates that pregnant BNP levels are approximately 2-fold higher than their nonpregnant counterparts, and do not significantly fluctuate during pregnancy. In conclusion, pregnancy is associated with a significant, but small increase in the BNP levels compared with nonpregnant women.
PMID: 19455566
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Monk BJ,Willmott LJ,Sumner DA
Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Chao Family Comprehensive Cancer Center, University of California Irvine Medical Center, Building 56, 101 The City Drive, Orange CA 92868, USA.
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Anti-angiogenesis agents in metastatic or recurrent cervical cancer.
Gynecol Oncol. 2009 Oct 25;:
While the incidence of cervical cancer has declined significantly in the United States, it still remains a serious American health threat. When detected early, cervical cancer is generally curable. Early lesions are treated surgically, and locally advanced lesions are managed with concurrent cisplatin chemotherapy and pelvic radiation. Metastatic disease or recurrent lesions not amenable to radical local excision or regional radiation are treated with palliative chemotherapy. Current chemotherapeutic regimens are associated with significant side effects and only limited activity making the identification of active and tolerable novel targeted agents a high priority. Angiogenesis is central to cervical cancer development and progression. The dominant role of angiogenesis in cervical cancer seems to be directly related to HPV inhibition of p53 and stabilization of HIF-1 alpha, both of which increase VEGF. Bevacizumab binding and subsequent inactivation of VEGF seem to shrink cervical tumors and delay progression without appreciable toxicity, and are therefore being studied in a Gynecologic Oncology Group (GOG) phase III trial. Other intracellular tyrosine kinase inhibitors (TKIs) of angiogenesis such as pazopanib are also encouraging, especially in lieu of their oral administration. Further study of angiogenesis and its inhibition are ongoing.
PMID: 19861227
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An WS,Kim HJ,Cho KH,Vaziri ND
Div. of Nephrology and Hypertension, UCI Medical Center, 101 The City Drive, Bldg. 53, Rm. 125, Rt. 81, Orange, CA 92868, USA.
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Omega-3 fatty acid supplementation attenuates oxidative stress, inflammation, and tubulointerstitial fibrosis in the remnant kidney.
Am J Physiol Renal Physiol. 2009 Oct;297(4):F895-903
Significant reduction of renal mass initiates a series of hemodynamic and nonhemodynamic events which lead to proteinuria, glomerulosclerosis, tubulointerstitial injury, and end-stage renal failure. Lipid mediators derived from fatty acids participate in regulation of renal hemodynamic and nonhemodynamic processes that influence progression of renal disease. Composition of cellular fatty acids and hence related signaling responses are influenced by their dietary contents. Consumption of omega-3 fatty acids (O-3FA) has proven effective in mitigating atherosclerosis. We tested the hypothesis that O-3FA supplementation may retard progression and attenuate upregulation of pathways involved in oxidative stress, inflammation, and fibrosis in rats with renal mass reduction. Sprague-Dawley rats were subjected to 5/6 nephrectomy [chronic renal failure (CRF)] and randomly assigned to the untreated and O-3FA-treated (0.3 g.kg(-1).day(-1) by gastric gavage for 12 wk) groups. Sham-operated rats served as controls. The untreated CRF rats exhibited proteinuria, hypertension, azotemia, upregulations of renal tissue NAD(P)H oxidase, MCP-1, COX-2, PAI-1, TGF-beta, Smad2, alpha-smooth muscle actin, fibronectin, and hepatocyte growth factor, activation of ERK1/2 and NF-kappaB, downregulation of Smad7, intense mononuclear leukocyte infiltration, tubulointerstitial fibrosis, and glomerulosclerosis. O-3FA supplementation significantly lowered COX-2, NAD(P)H oxidase (NOX-4, gp91(phox), p47(phox), p22(phox)), PAI-1, TGF-beta, connective tissue growth factor, alpha-smooth muscle actin, fibronectin, Smad2, and MCP-1, raised Smad7, and attenuated ERK1/2 and NF-kappaB activation, tubulointerstitial fibrosis, and inflammation. Thus, long-term O-3FA supplementation can reduce or reverse upregulation of prooxidant, proinflammatory, and profibrotic pathways and attenuate tubulointerstitial fibrosis in the remnant kidney.
PMID: 19656915
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Winovitch KC,Wing DA,Lagrew DC,Chung JH
Department of Obstetrics and Gynecology, University of California Irvine, Orange, CA, USA. mfm@uci.edu
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The risk of acute neonatal morbidities in the delivery room after primary cesarean at term: influence of labor and stage.
Am J Perinatol. 2009 Sep;26(8):545-51
We evaluated acute neonatal morbidities in the delivery room associated with primary cesarean performed prior to labor and in the first or second stages of labor. A retrospective cohort study was conducted on subjects undergoing term, primary cesareans at the Women's Pavilion, Miller Children's Hospital in Long Beach, California from 2000 to 2007. Acute neonatal morbidities were tabulated as a function of time during labor when cesarean was performed. Composite neonatal morbidity was defined as the presence of at least one of the following: low 5-minute Apgar score, need for intubation, and/or admission to neonatal intensive care unit. One thousand forty-five subjects delivered by cesarean without labor, 3098 in first stage, and 951 in second stage. Five-minute Apgar score < 7 was more common in cesareans performed during second stage than during first stage or without labor [3/1045 (0.3%) versus 28/3098 (0.9%) versus 12/951 (1.3%), P = 0.039]. Composite neonatal morbidity was not significantly different among the stages. Acute neonatal morbidities were not affected by the presence or absence of labor. Potential long-term sequelae require further study.
PMID: 19452426
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Mottow-Lippa L,Boker JR,Stephens F
The Gavin Herbert Eye Institute, University of California-Irvine, Irvine, California. Dr. Boker, formerly director of medical education research at University of California-Irvine, Irvine, CA 92697-4375, USA. llippa@uci.edu
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A prospective study of the longitudinal effects of an embedded specialty curriculum on physical examination skills using an ophthalmology model.
Acad Med. 2009 Nov;84(11):1622-30
PURPOSE: To prospectively evaluate effects of a longitudinal specialty curriculum on acquisition and retention of ophthalmic screening examination skills in a single class across three years of medical school (2004-2007). METHOD: Immediately after initial Year 2 skills training, preceptors evaluated students' (N=84) acquisition of basic eye screening examination skills. Similarly, the students self-assessed their skills. In Year 3, a required ophthalmology small-group module during the family medicine (FM) clerkship reinforced these skills. The authors audited history and physicals in two Year 3 clerkships and in one Year 4 subinternship to evaluate charted examination performance. They objectively assessed simulator-based ophthalmoscopy post-FM clerkship and post-Year 3 training. RESULTS: Preceptors rated 100% of students competent in all eye examination modalities post initial training; 98% of students self-rated themselves competent in disc visualization. An expert auditor found documented FM funduscopies (46%) surpassed those in a prior observational study (11%). Funduscopic retraining significantly improved performance on post-Year 3 objective assessment (mean score 55% retrained versus 19% nonretrained, P=.0005). However, 43% of FM and 91% of internal medicine workups reflected inadequate overall eye evaluations. Subinternship notes documented muscle excursions in 95% and pupils in 71% but recorded no funduscopies. CONCLUSIONS: Additional training successfully reinforced skills performance, which nonetheless decayed when not habitually practiced. Neither physical diagnosis preceptor ratings nor excellent performance in the FM ophthalmology module predicted subsequent skills performance in other clerkships or on simulator testing. The present study supports a reiterative retraining model for teaching this and other specialty physical examination skills.
PMID: 19858827
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Jester JV,Ling J,Harbell J
Gavin Herbert Eye Institute, University of California Irvine School of Medicine, Orange, CA.
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Measuring Depth of Injury (DOI) in an Isolated Rabbit Eye Irritation Test (IRE) using Biomarkers of Cell Death and Viability.
Toxicol In Vitro. 2009 Oct 23;:
While DOI is a mechanistic correlate to the ocular irritation response, attempts to measure DOI in alternative tests have been limited to qualitative histopathologic assessment by veterinarian pathologists. The purpose of this study was to determine whether DOI could be measured objectively by fluorescent staining for biomarkers of cell death and viability using an ex vivo isolated rabbit eye (IRE) test. A panel of nine materials characterized by in vivo DOI were selected that caused slight (3% acetic acid and 5% SDS), mild (acetone, sodium hypoclorate and 10% acetic acid), moderate (cyclohexanol and parafluoranaline) and severe (8% sodium hydroxide and 10% benzalkonium chloride) irritation. Materials were then tested using a modified IRE test with 3 hours recovery and then processed for cyrosectioning and staining using a TUNEL assay to detect cell death, phalloidin to detect intracellular f-actin and DAPI staining to detect nuclei. Control eyes treated with water showed intense phalloidin staining of the corneal epithelium and stromal keratocytes but no TUNEL labeling. In general, eyes treated with mild, moderate and severe irritants showed regions of TUNEL labeled epithelial and keratocyte nuclei with no phalloidin stain overlying phalloidin stained, undamaged cells. DOI measurements showed that slight irritants damaged <40% of the epithelium, mild and moderate irritants damaged >50% of the epithelium, extending at times into the anterior stroma (<20%), and the severe irritant damaged >50% of the stroma. Regression analysis between ex vivo and in vivo DOI showed a significant (p<0.007) correlation (r=0.785). These data suggest that fluorescent staining of fixed and sectioned tissue using biomarkers can be used to objectively identify the depth of injury caused by ocular irritants.
PMID: 19857567
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Monk BJ,Sill MW,McMeekin DS,Cohn DE,Ramondetta LM,Boardman CH,Benda J,Cella D
University of California, Irvine Medical Center, Orange, CA 92868, USA. bjmonk@uci.edu
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Phase III trial of four cisplatin-containing doublet combinations in stage IVB, recurrent, or persistent cervical carcinoma: a Gynecologic Oncology Group study.
J Clin Oncol. 2009 Oct 1;27(28):4649-55
PURPOSE: Assess toxicity and efficacy of cisplatin (Cis) doublet combinations in advanced and recurrent cervical carcinoma. PATIENTS AND METHODS: Patients were randomly assigned to paclitaxel 135 mg/m(2) over 24 hours plus Cis 50 mg/m(2) day 2 every 3 weeks (PC, reference arm); vinorelbine 30 mg/m(2) days 1 and 8 plus Cis 50 mg/m(2) day 1 every 3 weeks (VC); gemcitabine 1,000 mg/m(2) day 1 and 8 plus Cis 50 mg/m(2) day 1 every 3 weeks (GC); or topotecan 0.75 mg/m(2) days 1, 2, and 3 plus Cis 50 mg/m(2) day 1 every 3 weeks (TC). Survival was the primary end point with a 33% improvement relative to PC considered important (85% power, alpha = 5%). Quality-of-life data were prospectively collected. RESULTS: A total of 513 patients were enrolled when a planned interim analysis recommended early closure for futility. The experimental-to-PC hazard ratios of death were 1.15 (95% CI, 0.79 to 1.67) for VC, 1.32 (95% CI, 0.91 to 1.92) for GC, and 1.26 (95% CI, 0.86 to 1.82) for TC. The hazard ratios for progression-free survival (PFS) were 1.36 (95% CI, 0.97 to 1.90) for VC, 1.39 (95% CI, 0.99 to 1.96) for GC, and 1.27 (95% CI, 0.90 to 1.78) for TC. Response rates (RRs) for PC, VC, GC, and TC were 29.1%, 25.9%, 22.3%, and 23.4%, respectively. The arms were comparable with respect to toxicity except for leucopenia, neutropenia, infection, and alopecia. CONCLUSION: VC, GC, and TC are not superior to PC in terms of overall survival (OS). However, the trend in RR, PFS, and OS favors PC. Differences in chemotherapy scheduling, pre-existing morbidity, and toxicity are important in individualizing therapy.
PMID: 19720909
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Reavis KM
Division of Gastrointestinal Surgery, Department of Surgery, University of California, Irvine Medical Center, Orange, CA 92868, USA. kreavis@uci.edu
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The esophageal anastomosis: how improving blood supply affects leak rate.
J Gastrointest Surg. 2009 Sep;13(9):1558-60
PMID: 19415398
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Miller RB
Department of Medicine, School of Medicine, College of Health Sciences, University of California, Irvine, USA. rbmiller@uci.edu
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Physician orders to supplement advance directives: rescuing patient autonomy.
J Clin Ethics. 2009;20(3):212-9
To adapt Churchill's comment on democracy, "No one pretends that [POLSTs are] perfect..." but physicians' orders about life-sustaining treatments are a very important supplement to advance directives, especially for patients who are extremely or terminally ill, and most particularly for patients who require emergency treatment by first responders or by physicians who do not know them as persons. The standardized orders of limited options, however, are no substitute for a detailed treatment directive of a patient with a known illness, with predictable trajectories and complications. And, in this latter circumstance, a thoroughly informed proxy may also assist physicians in selecting appropriate treatment for patients who have lost decisional capacity and/or the ability to express it. I believe all patients should have an advance directive, preferably a combined proxy-treatment directive, and preferably one that has been thoroughly discussed with the attending physician and with the proxy, successor proxies, and preferably relatives and friends. Nurses, social workers, and chaplains may be very helpful to the patient in thinking through his or her preferences, especially if the severity of illness and the limited efficacy of interventions are such that the patient would wish to omit life-sustaining treatment or to discontinue it after a time-limited trial. Finally, because POLST is new or yet to be initiated in many areas of the country, it behooves all physicians to become knowledgeable of POLST and to initiate discussion of it with colleagues, patients, patients' proxies, and with relatives of patients. Even more recent is the combined advance directive/physician's orders to permit natural dying, actionable immediately for patients suffering severely and irremediably, but actionable at a future time if the patient progresses to advanced stages of dementia or other devastating brain disorders. In order to encourage physicians to initiate advance care planning with their patients, this quote from a patient shortly before his death from prostatic cancer might prove helpful: "Not every patient can be saved, but his illness can be eased by the way that the doctor responds to him. In learning to talk to his patients, the doctor may talk himself back into loving his work. He has little to lose and everything to gain by letting the sick man into his heart. If he does, they can share--as few others can--the wonder, terror, and exultation of being on the edge of being"
PMID: 19845191
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Baldi P,Hirschberg DS
School of Information and Computer Sciences, Institute for Genomics and Bioinformatics, University of California Irvine, Irvine, CA 92697-3435, USA. pfbaldi@ics.uci.edu
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An intersection inequality sharper than the tanimoto triangle inequality for efficiently searching large databases.
J Chem Inf Model. 2009 Aug;49(8):1866-70
Bounds on distances or similarity measures can be useful to help search large databases efficiently. Here we consider the case of large databases of small molecules represented by molecular fingerprint vectors with the Tanimoto similarity measure. We derive a new intersection inequality which provides a bound on the Tanimoto similarity between two fingerprint vectors and show that this bound is considerably sharper than the bound associated with the triangle inequality of the Tanimoto distance. The inequality can be applied to other intersection-based similarity measures. We introduce a new integer representation which relies on partitioning the fingerprint components, for instance by taking components modulo some integer M and reporting the total number of 1-bits falling in each partition. We show how the intersection inequality can be generalized immediately to these integer representations and used to search large databases of binary fingerprint vectors efficiently.
PMID: 19601605
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Pahl MV,Ni Z,Sepassi L,Moradi H,Vaziri ND
Division of Nephrology and Hypertension, University of California, Irvine, CA, USA. mpahl@uci.edu
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Plasma phospholipid transfer protein, cholesteryl ester transfer protein and lecithin:cholesterol acyltransferase in end-stage renal disease (ESRD).
Nephrol Dial Transplant. 2009 Aug;24(8):2541-6
BACKGROUND: Chronic kidney disease (CKD) results in accelerated atherosclerosis that is primarily caused by inflammation, oxidative stress and impaired triglyceride and HDL metabolisms. Several plasma proteins including phospholipid transfer protein (PTLP), cholesteryl ester transfer protein (CETP) and lecithin:cholesterol acyltransferase (LCAT) affect HDL metabolism. PLTP transfers phospholipids and free cholesterol from triglyceride-rich lipoproteins to HDL, phospholipids between HDL particles and facilitates cholesterol efflux from cells. CETP catalyzes the transfer of cholesteryl esters from HDL to LDL in exchange for triglycerides, and LCAT catalyzes esterification of free cholesterol on the surface of HDL. Given the role of these proteins in the regulation of HDL metabolism, we examined the effect of ESRD on plasma PLTL, CETP and LCAT. METHODS: A group of 21 stable ESRD patients maintained on haemodialysis and a group of 21 age-matched normal control individuals were included in the study. Plasma apolipoprotein A-1, PLTP, CETP and LCAT levels were measured. RESULTS: Plasma triglyceride concentration was elevated and plasma HDL cholesterol, apolipoprotein A-1 and LCAT concentrations were significantly reduced, whereas plasma PLTP and CETP concentrations and activities were unchanged in the ESRD patients. CONCLUSIONS: These findings point to acquired LCAT and Apo A-1 deficiencies and tend to exclude dysregulation of PLTP or CETP in the pathogenesis of HDL abnormalities in haemodialysis patients.
PMID: 19297356
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Phalen RF,Mendez LB
Department of Community and Environmental Medicine, School of Medicine, University of California, Irvine, CA 92697-1825, USA. rfphalen@uci.edu
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Dosimetry considerations for animal aerosol inhalation studies.
Biomarkers. 2009 Jul;14 Suppl 1:63-6
The determination of the dose of inhaled aerosol particles in animal subjects is not a trivial exercise. In its simplest form, the dose is the amount (particle number, mass or other relevant metric) that deposits in the respiratory tract. The amount deposited will depend on the aerosol particle sizes (e.g. the aerodynamic diameter size distribution), the duration of exposure, the exposure system's delivery efficiency, the subject's ventilation rate, the species and strain, and other factors. Similarly, species differences in the clearance rates of deposited particles will influence the time integrated particle doses. In practice, particle doses are estimated using mathematical models, previous experimental dosimetry data, tracers of the inhaled particles and biomarkers of exposure. With care, desired aerosol doses can be achieved and documented.
PMID: 19604062
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Moore MJ,Suda T,Oiwa K
Bren School of Information and Computer Science, University of California, Irvine, Irvine, CA 92697, USA. mikemo@ics.uci.edu
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Molecular communication: modeling noise effects on information rate.
IEEE Trans Nanobioscience. 2009 Jun;8(2):169-80
Molecular communication is a new paradigm for communication between biological nanomachines over a nano- and microscale range. As biological nanomachines (or nanomachines in short) are too small and simple to communicate through traditional communication mechanisms (e.g., through sending and receiving of radio or infrared signals), molecular communication provides a mechanism for a nanomachine (i.e., a sender) to communicate information by propagating molecules (i.e., information molecules) that represent the information to a nanomachine (i.e., a receiver). This paper describes the design of an in vitro molecular communication system and evaluates various approaches to maximize the probability of information molecules reaching a receiver(s) and the rate of information reaching the receiver(s). The approaches considered in this paper include propagating information molecules (diffusion or directional transport along protein filaments), removing excessive information molecules (natural decay or receiver removal of excessive information molecules), and encoding and decoding approaches (redundant information molecules to represent information and to decode information). Two types of molecular communication systems are considered: a unicast system in which a sender communicates with a single receiver and a broadcast system in which a sender communicates with multiple receivers. Through exploring tradeoffs among the various approaches on the two types of molecular communication systems, this paper identifies promising approaches and shows the feasibility of an in vitro molecular communication system.
PMID: 19535324
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Fielder TJ,Barrios L,Montoliu L
Transgenic Mouse Facility, University Laboratory Animal Resources, University of California-Irvine, Irvine, CA, 92697-1310, USA.
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A survey to establish performance standards for the production of transgenic mice.
Transgenic Res. 2009 Oct 20;:
The generation of transgenic mice by microinjection of DNA into the pronuclei of fertilized oocytes was described in the early 1980s. A number of parameters affecting the efficiency of the technique were soon identified, including the type of DNA construct, the concentration of DNA being injected, and, most importantly, the strain of mice used for oocyte donors. Since then, hundreds of laboratories and transgenic core facilities across the world have successfully used this technique, essentially as originally described, to create thousands of new transgenic mouse lines. However, the overall procedure continues to be relatively inefficient, in terms of the number of fertilized oocytes required to produce a transgenic mouse, and variations in yields from day to day and construct to construct can be large. Consequently, core facilities often struggle to explain to their customers why a sufficient number of transgenic founders were not produced from a given construct. We believe the field (and individual facilities) would benefit from a rigorous assessment of average yields and expected variations in yields. To this end, we have initiated a survey from the International Society for Transgenic Technologies (ISTT) web site ( www.transtechsociety.org ), to obtain raw microinjection data from as many facilities as possible. We intend to use this data to establish performance standards for the field. Existing facilities will be able to refer to these standards in dealing with dissatisfied clients, and new facilities will be able to aim for an achievable goal. We may even be able to discover an optimum combination of factors that will allow every facility to achieve higher yields.
PMID: 19842055
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Yamamoto M,Hayashi MS,Nguyen NT,Nguyen TD,McCloud S,Imagawa DK
Division of Hepatobiliary and Pancreas Surgery, Islet Cell Transplantation, Department of Surgery, University of California-Irvine Medical Center, 333 City Blvd W, Ste 1205, Orange, CA 92868. dkimagaw@uci.edu.
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Use of seamguard to prevent pancreatic leak following distal pancreatectomy.
Arch Surg. 2009 Oct;144(10):894-9
OBJECTIVE: To investigate the use of Seamguard, a bioabsorbable staple line-reinforcement product, to prevent pancreatic leak after distal pancreatectomy. Design, Setting, and PARTICIPANTS: A retrospective study examined 85 consecutive patients undergoing distal pancreatectomy at an academic institution from September 5, 1997, to September 30, 2007. MAIN OUTCOME MEASURES: Pancreatic fistula and overall mortality and morbidity. RESULTS: In February 2004, the use of Seamguard in distal pancreas resections was introduced at our institution. Indications for resection included trauma (11 patients), neoplasms (62 patients), and chronic pancreatitis (12 patients). Pancreatic leak was defined as drain output of 25 mL/d or more 7 days postoperatively with a drain amylase level of 1000 U/L or more. Pancreatic leak occurred in 10 of 38 patients (26%) undergoing conventional resection with suture ligation of the pancreatic duct or nonreinforced stapled resection vs 2 of 47 patients (4%) undergoing staple resection using Seamguard reinforcement. Multivariate analysis showed that use of Seamguard with the stapler independently decreased the risk for pancreatic fistula after distal pancreatectomy (odds ratio, 0.07; 95% confidence interval, 0.01-0.43; P = .01). CONCLUSIONS: The use of Seamguard is quickly becoming a common adjunct in distal pancreas resections. Our study shows a lower incidence of pancreatic leak after distal pancreatectomy with the use of this staple line-reinforcing product.
PMID: 19841355
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