Pevzner L,Rayburn WF,Rumney P,Wing DA
Departments of Obstetrics and Gynecology, University of California, Irvine, Orange, 92869, USA. mfm@uci.edu
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Factors predicting successful labor induction with dinoprostone and misoprostol vaginal inserts.
Obstet Gynecol. 2009 Aug;114(2 Pt 1):261-7
OBJECTIVE: To evaluate the maternal and pregnancy characteristics that independently predict successful induction of labor, defined as vaginal delivery. METHODS: The study was a secondary analysis of the data collected during the Misoprostol Vaginal Insert Trial, a multisite, double-blind, randomized trial of women requiring cervical ripening before induction of labor. The primary outcome was to estimate the maternal and pregnancy characteristics that independently predict successful induction of labor. Univariable and multiple regression analyses were performed for maternal and pregnancy-related factors that potentially could predict a successful induction of labor. RESULTS: A total of 1,274 patients had sufficient labor and delivery data for a comparative analysis. Nine hundred sixteen (72%) induced patients subsequently had vaginal deliveries. Multiparity (odds ratio [OR] 4.63, 95% confidence interval [CI] 3.39-6.32, P<.001), maternal body mass index (BMI) less than 30 (OR 1.69, 95% CI 1.32-2.22, P<.001) and height greater than 5'5" (OR 1.47, 95% CI 1.15-1.9, P=.002), baseline modified Bishop score of 4 (OR 2.15, 95% CI 1.12-4.20, P=.047), and birth weight below 4,000 g (OR 2.17, 95% CI 1.51-3.13, P<.001) were significant for predicting successful induction of labor. Logistic regression analysis was performed to evaluate each factor as an independent predictor. In addition to the above-mentioned factors, maternal age younger than 35 years (OR 1.81, 95% CI 1.15-2.86, P=.01) and Hispanic race (OR 1.45, 95% CI 1.02-2.05, P=.036) each proved to significantly favor a successful induction. Conversely, African-American race was correlated with a higher incidence of cesarean delivery (OR 1.47, 95% CI 1.02-2.13, P<.001). CONCLUSION: Maternal characteristics such as BMI, parity, age, and race and neonatal birth weight are important variables to consider when predicting a successful induction of labor. The nearly 30% rate of cesarean delivery in this study underscores the importance of selecting appropriate candidates. LEVEL OF EVIDENCE: II.
PMID: 19622986
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Scholz T,Krichevsky A,Sumarto A,Jaffurs D,Wirth GA,Paydar K,Evans GR
Aesthetic and Plastic Surgery Institute, University of California, Irvine, Orange, CA, USA. tscholz@uci.edu
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Peripheral nerve injuries: an international survey of current treatments and future perspectives.
J Reconstr Microsurg. 2009 Jul;25(6):339-44
Peripheral nerve injuries are a serious health concern and leave many patients with lifelong disabilities. There is little information about incidences, current practice, outcomes, and type of research that may help delineate new strategies. A questionnaire was designed to determine characteristics of peripheral nerve injuries and the need for alternative strategies and sent to 889 plastic, hand, trauma, and orthopedic surgeons in 49 countries; 324 completed surveys were collected and analyzed (total response rate of 36.45%). The majority of institutions treat more than 3000 patients annually. Trauma was the leading cause of injury with the majority located on the upper extremity. In most cases, a primary repair was achieved, but 2.52% were unrepairable. The overall outcome was linked to their Sunderland classification (SCL). A grade 1 nerve injury (SCL-1) reached a maximum outcome after 7.15 months. SCL-2, -3, -4, and -5 needed 10.69, 14.08, 17.66, and 19.03 months, respectively. Tissue engineering was considered the most important research field, resulting in a visual analogue scale of 8.6. Despite marked advances in the treatment of peripheral nerve injuries, clinical outcomes still appear unsatisfactory. The importance of research in the field of tissue engineering should be emphasized as a pathway toward improving these outcomes.
PMID: 19301234
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Nitta T,Hofacre A,Hull S,Fan H
Cancer Research Institute, Department of Molecular Biology and Biochemistry, University of California Irvine, Irvine, California.
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IDENTIFICATION AND MUTATIONAL ANALYSIS OF A REJ RESPONSE ELEMENT IN JAAGSIEKTE SHEEP RETROVIRUS RNA.
J Virol. 2009 Sep 23;:
Jaagsiekte sheep retrovirus (JSRV) is a simple betaretrovirus causing a contagious lung cancer of sheep. JSRV encodes unspliced and spliced viral RNAs, among which unspliced RNA encodes Gag and Pol proteins, and a singly spliced mRNA encodes Env protein. In another study we found that JSRV encodes a regulatory protein Rej that is responsible for synthesis of Gag polyprotein from unspliced viral RNA. Rej is encoded in 5' end of env and it enhances nuclear export or accumulation of cytoplasmic unspliced viral RNA in 293T cells but not most other cell lines ( Hofacre, et al., submitted). In this study, we found that mutations in the 3' end of the env in the context of a CMV-driven full length JSRV expression construct abolished Gag protein synthesis and released viruses in 293T cells. These mutants also showed deficits in accumulation of unspliced viral RNA in the cytoplasm. These mutants defined a Rej responsive elemnt (RejRE). Inhibition of CRM1 but not Tap function prevented nuclear export/accumulation of cytoplasmic unspliced RNA in 293T cells, similar to other complex retroviruses that express analogous regulator proteins (e.g. HIV Rev). Structural modeling of the RejRE with Zuker mFold indicated a region with a predicted stable secondary structure. Mutational analysis in this region indicated the importance of both secondary structures and primary nucleotide sequences in a central stem-bulge-stem structure. In contrast to 293T cells, mutations in the RejRE did not affect the levels of cytoplasmic unspliced RNA in 293 cells, although the unspliced RNA showed partial degradation, perhaps due to lack of translation. RejRE-containing RNA relocalized Rej protein from the nucleus to the cytoplasm in 293 and rat 208F cells, suggesting binding of Rej to the RejRE.
PMID: 19776134
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Frade Mera MJ,Guirao Moya A,Esteban Sánchez ME,Rivera Alvarez J,Cruz Ramos AM,Bretones Chorro B,Viñas Sánchez S,Jacue Izquierdo S,Montane López M
Servicio de Medicina Intensiva UCI Polivalente. Hospital Universitario 12 de Octubre. Madrid. Espaņa.
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[Analysis of 4 sedation rating scales in the critical patient.]
Enferm Intensiva. 20(3):88-94
BACKGROUND: This study aimed to verify the relationship between different Sedation Rating Scales (SRSs) for critical patients on mechanical ventilation and to know the relationship between the SRSs, clinical information and the dose of sedative and analgesia drugs (SAD). MATERIAL AND METHODS: A longitudinal, prospective analytic pilot study conducted in a Medical-Surgical Intensive Care Unit of a tertiary hospital from October-December 2006. The sample included patients who required administration of SAP and mechanical ventilation. The following biological parameters and scales were evaluated: patient's demographics, RAMSAY, Sedation Agitation Scale (SAS), Richmond Agitation Sedation Scale (RASS), Motor Activity Assessment Scale (MASS), SAD dose, mean blood pressure, cardiac rate, pupil diameter and respiratory frequency. Spearman coefficient of interrelation was used to compare the relationship between the different scales. RESULTS: A total of 2.412 measurements were made for each variable: SRS, clinical information and SAD dose in 30 patients with different diseases, 63 % males, age 52 +/- 19 years, APACHEII 24 +/- 8, SAPSII 44 +/- 16, with an ICU mortality UCI 34 %. Median and IQ range of stay in ICU 15.5 and 20 days, of mechanical ventilation 9 and 14 days, of SAD 6 and 5.5 days and of paralyzing drugs (PD) 2 and 5 days, respectively. Interrelation was detected between all the SRSs, with p < 0.0001. The relationship between SAS, RASS and MASS was direct, whereas these were related inversely to RAMSAY. No evidence of interrelation was found between the SRSs, the clinical information and the SAD doses. CONCLUSION. The RAMSAY scale that has not been validated in ICU patients has a strong interrelation with the other already validated SRSs. SRSs are subjective and do not correlate with the clinical information and the SAD doses, probably due to the sample's small size and heterogeneity.
PMID: 19775565
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Farid M,Steinert RF,Gaster RN,Chamberlain W,Lin A
Department of Ophthalmology, The Gavin Herbert Eye Institute, University of California-Irvine, CA 92697, USA.
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Comparison of penetrating keratoplasty performed with a femtosecond laser zig-zag incision versus conventional blade trephination.
Ophthalmology. 2009 Sep;116(9):1638-43
PURPOSE: To evaluate visual outcomes and astigmatism in patients who underwent penetrating keratoplasty (PK) with 2 different incision techniques. DESIGN: Retrospective comparison of a consecutive surgical series. PARTICIPANTS: Fifty-seven consecutive patients who underwent PK at the University of California, Irvine, academic referral practice. METHODS: A comparison of 49 eyes of 43 patients that underwent femtosecond laser zig-zag incision pattern PK versus 17 eyes of 14 patients that underwent conventional Barron suction trephination PK performed contemporaneously. All PKs were closed with an identical, 24-bite running nylon suture technique. MAIN OUTCOME MEASURES: Topographically determined astigmatism, best spectacle-corrected visual acuity (BSCVA), and recovery of full visual potential. RESULTS: The postoperative follow-up ranged from 1 to 12 months. There was a significant difference in average astigmatism between the groups at postoperative month 1 (P = 0.013) and 3 (P = 0.018). By month 3, the average astigmatism was 3 diopters (D) in the zig-zag group and 4.46 D in the conventional group. Of the patients with normal macular and optic nerve function (n(ZZ) = 32; n(con) = 14), a significant difference in BSCVA was seen at month 1 (P = 0.0003) and month 3 (P = 0.006) with 81% of the zig-zag group versus 45% of the conventional group achieving BSCVA of > or =20/40 by month 3 (P = 0.03). CONCLUSIONS: The femtosecond laser generated zig-zag-shaped incision results in a more rapid recovery of BSCVA and induces less astigmatism compared with conventional blade trephination PK. FINANCIAL DISCLOSURE(S): Proprietary commercial disclosure may be found after the references.
PMID: 19646760
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Brody JP
Department of Biomedical Engineering University of California Irvine, Irvine, California, United States of America. jpbrody@uci.edu
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Parallel routes of human carcinoma development: implications of the age-specific incidence data.
PLoS One. 2009;4(9):e7053
BACKGROUND: The multi-stage hypothesis suggests that cancers develop through a single defined series of genetic alterations. This hypothesis was first suggested over 50 years ago based upon age-specific incidence data. However, recent molecular studies of tumors indicate that multiple routes exist to the formation of cancer, not a single route. This parallel route hypothesis has not been tested with age-specific incidence data. METHODOLOGY/PRINCIPAL FINDINGS: To test the parallel route hypothesis, I formulated it in terms of a mathematical equation and then tested whether this equation was consistent with age-specific incidence data compiled by the Surveillance Epidemiology and End Results (SEER) cancer registries since 1973. I used the chi-squared goodness of fit test to measure consistency. The age-specific incidence data from most human carcinomas, including those of the colon, lung, prostate, and breast were consistent with the parallel route hypothesis. However, this hypothesis is only consistent if an immune sub-population exists, one that will never develop carcinoma. Furthermore, breast carcinoma has two distinct forms of the disease, and one of these occurs at significantly different rates in different racial groups. CONCLUSIONS/SIGNIFICANCE: I conclude that the parallel route hypothesis is consistent with the age-specific incidence data only if carcinoma occurs in a distinct sub population, while the multi-stage hypothesis is inconsistent with this data.
PMID: 19774079
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Tsui YK,Tsai FY,Hasso AN,Greensite F,Nguyen BV
Department of Radiological Sciences, University of California Irvine Medical Center, 101 City Drive South, Orange, CA 92868, USA; Department of Radiology, Chi Mei Medical Center, Yong-Kang City, Tainan, Taiwan.
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Susceptibility-weighted imaging for differential diagnosis of cerebral vascular pathology: A pictorial review.
J Neurol Sci. 2009 Sep 19;:
Susceptibility-weighted imaging (SWI) is a high-spatial resolution, three-dimensional, gradient-echo (GRE) magnetic resonance (MR) technique. This fully velocity-compensated pulse sequence utilizes the magnetic susceptibility differences of various tissues or substances, such as blood products, iron, and calcification. By postprocessing the magnitude images using a phase mask, it emphasizes the magnetic properties of different susceptibility effects. Generated minimal intensity projection (minIP) images can further demonstrate tortuous vasculature and the continuity of vessels or abnormalities across slices. SWI has been used to improve the diagnosis of neurological trauma, brain neoplasm, neurodegenerative disorders, and cerebrovascular disease because of its ability to demonstrate microbleeds and conspicuity of the veins and other sources with susceptibility effects. We have used SWI to identify cerebrovascular lesions which may be obscured on other MR sequences to aid in the differential diagnosis. We present a review with selected cases to demonstrate the usefulness of this new neuroimaging technique in improving the diagnosis of cerebral vascular pathology.
PMID: 19772973
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Chase DM,Rincon A,Deane M,Tewari KS,Brewster WR
Division of Gynecologic Oncology, Chao Family Comprehensive Cancer Center, University of California Irvine Medical Center, Orange, CA, USA.
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Socioeconomic factors may contribute to neoadjuvant chemotherapy use in metastatic epithelial ovarian carcinoma.
Gynecol Oncol. 2009 Sep 21;:
OBJECTIVE.: To identify patient characteristics which predict receipt of neoadjuvant chemotherapy (NCT) versus standard therapy (ST) in metastatic ovarian cancer. METHODS.: A retrospective matched case control study was conducted of 52 women treated with NCT compared to 104 women who received standard treatment from 1996 to 2007. The t test was used for comparison of means between the groups, and the chi(2) test was used for categorical data. Multivariable analysis was performed with logistic regression models and only two-tailed analyses with a P value <0.05 were considered statistically significant. RESULTS.: Age, employment and marital status, and insurance alone did not affect treatment allocation (P=NS). However, non-Hispanic White (NHW) patients were more as likely to receive ST (P<0.05). When insurance was stratified by ethnicity, NHW patients were twice as likely to have private insurance (OR=2.29, CI=1.16-4.53). Furthermore, medically compromised (MC) patients who were NHW were almost three times more likely to receive ST (OR=2.72, CI=1.02-5.00). In multivariate analysis, only MC and publically funded women were more likely to receive NCT (OR 3.83 CI=1.35-11.11); P=0.01). During surgery, patients receiving NCT were found to have smaller tumors and less ascites, and were more likely to be optimally debulked with lower estimated blood loss and shorter hospital stays. The median survival for ST was 55.8 months versus 26 months for NCT (P<0.001). CONCLUSIONS.: Non-clinical factors such as publically funded status and non-Hispanic White race may influence the allocation of NCT for women with metastatic ovarian cancer.
PMID: 19772939
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Kahn C
Department of Emergency Medicine, University of California-Irvine, Irvine, CA, USA.
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Commentary: moving forward by looking behind you.
Ann Emerg Med. 2009 Oct;54(4):604-5
PMID: 19769889
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Lander AD
Center for Complex Biological Systems, Department of Developmental and Cell Biology, and Department of Biomedical Engineering, University of California at Irvine, Irvine, CA 92697-2300. adlander@uci.edu.
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The 'stem cell' concept: is it holding us back?
J Biol. 2009 Sep 21;8(8):70
ABSTRACT: Developmental biology, regenerative medicine and cancer biology are increasingly occupied with the molecular characterization of stem cells. Yet recent work adds to a growing body of literature suggesting that 'stemness' cannot be reduced to the molecular features of cell types, and is instead an emergent property of cell lineages under feedback control.
PMID: 19769787
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Sassoon CS,Caiozzo VJ
Department of Medicine, University of California, Irvine, California, USA. csassoon@uci.edu.
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Bench-to-bedside review: Diaphragm muscle function in disuse and acute high-dose corticosteroid treatment.
Crit Care. 2009 Sep 8;13(5):221
ABSTRACT: Critically ill patients may require mechanical ventilatory support and short-term high-dose corticosteroid to treat some specific underlying disease processes. Diaphragm muscle inactivity induced by controlled mechanical ventilation produces dramatic alterations in diaphragm muscle structure and significant losses in function. Although the exact mechanisms responsible for losses in diaphragm muscle function are still unknown, recent studies have highlighted the importance of proteolysis and oxidative stress. In experimental animals, short-term strategies that maintain partial diaphragm muscle neuromechanical activation mitigate diaphragmatic force loss. In animal models, studies on the influence of combined controlled mechanical ventilation and short-term high-dose methylprednisolone have given inconsistent results in regard to the effects on diaphragm muscle function. In the critically ill patient, further research is needed to establish the prevalence and mechanisms of ventilator-induced diaphragm muscle dysfunction, and the possible interaction between mechanical ventilation and the administration of high-dose corticosteroid. Until then, in caring for these patients, it is imperative to allow partial activation of the diaphragm, and to administer the lowest dose of corticosteroid for the shortest duration possible.
PMID: 19769782
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Rajan PV,Chung JH,Porto M,Wing DA
Department of Obstetrics and Gynecology, University of California, Irvine, Orange, California 92868, USA. mfm@uci.edu
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Correlation of increased fetal asymmetry with shoulder dystocia in the nondiabetic woman with suspected macrosomia.
J Reprod Med. 2009 Aug;54(8):478-82
OBJECTIVE: To determine if the sonographic difference of > or = 2.6 cm between the fetal abdominal diameter (AD) and biparietal diameter (BPD), a proxy for fetal asymmetry, has an association with shoulder dystocia in nondiabetic women with suspected macrosomia. STUDY DESIGN: A retrospective cohort study was performed in 3 Southern California tertiary care hospitals. We identified patients in whom sonographic evaluation after 36 weeks' gestation demonstrated an estimated fetal weight > 4,000 g. Additional prenatal and delivery information was obtained from hospital records. RESULTS: We identified 159 subjects who met ultrasound criteria and underwent a vaginal delivery. The mean AD-BPD difference in the shoulder dystocia group was significantly greater than in the group without shoulder dystocia (2.76 +/- 0.59 vs. 2.37 +/- 0.56, p = 0.001). The adjusted OR of shoulder dystocia in the group with an AD-BPD difference > or = 2.6 was 3.67 (95% CI, 1.44-9.36). CONCLUSION: Significant discordance between the fetal head and abdomen appears to be associated with an increased rate of shoulder dystocia in a nondiabetic population with suspected macrosomia.
PMID: 19769192
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Colt H,Murgu SD,Ahn YC,Brenner M
University of California School of Medicine, Pulmonary and Critical Care Medicine, Department of Medicine, 101 the City Drive South, Building 53, Room 119, Route 81 Orange, California 92868, USA. hcolt@uci.edu
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Multimodality bronchoscopic imaging of tracheopathica osteochondroplastica.
J Biomed Opt. 14(3):034035
Results of a commercial optical coherence tomography system used as part of a multimodality diagnostic bronchoscopy platform are presented for a 61-year-old patient with central airway obstruction from tracheopathica osteochondroplastica. Comparison to results of white-light bronchoscopy, histology, and endobronchial ultrasound examination are accompanied by a discussion of resolution, penetration depth, contrast, and field of view of these imaging modalities. White-light bronchoscopy revealed irregularly shaped, firm submucosal nodules along cartilaginous structures of the anterior and lateral walls of the trachea, sparing the muscular posterior membrane. Endobronchial ultrasound showed a hyperechoic density of 0.4 cm thickness. optical coherence tomography (OCT) was performed using a commercially available, compact time-domain OCT system (Niris System, Imalux Corp., Cleveland, Ohio) with a magnetically actuating probe (two-dimensional, front imaging, and inside actuation). Images showed epithelium, upper submucosa, and osseous submucosal nodule layers corresponding with histopathology. To our knowledge, this is the first time these commercially available systems are used as part of a multimodality bronchoscopy platform to study diagnostic imaging of a benign disease causing central airway obstruction. Further studies are needed to optimize these systems for pulmonary applications and to determine how new-generation imaging modalities will be integrated into a multimodality bronchoscopy platform.
PMID: 19566328
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Kravitz BA,Corrada MM,Kawas CH
Department of Neurobiology and Behavior, University of California at Irvine, Irvine, CA, USA. bkravitz@uci.edu
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Elevated C-reactive protein levels are associated with prevalent dementia in the oldest-old.
Alzheimers Dement. 2009 Jul;5(4):318-23
BACKGROUND: C-reactive protein (CRP) is a nonspecific marker of inflammation that is increased in the brain and serum of patients with Alzheimer's disease (AD), and has been associated with increased risk of developing dementia. Inflammation increases with age, and the number of people reaching age 90 years and older is growing, making the association between inflammation and dementia increasingly relevant. Using a cross-sectional design, we examined whether high levels of serum CRP are associated with increased odds of prevalent dementia in the oldest-old. METHODS: Serum CRP levels of 305 participants (mean age +/- standard deviation, 94.3 +/- 2.9 years) from the 90+ Study, a longitudinal cohort study of people aged 90 years and older, were evaluated with respect to all-cause dementia. Levels of CRP were divided into three categories: undetectable (<0.5 mg/dL), detectable (0.5-0.7 mg/dL), and elevated (> or =0.8 mg/dL). Odds ratios (ORs) were calculated using logistic regression, and were adjusted for covariates. RESULTS: Relative to participants with undetectable CRP levels, participants with detectable or elevated CRP levels had increased odds of all-cause dementia (detectable: OR, 3.0; 95% confidence interval, 1.2-7.3; elevated: OR, 5.0; 95% confidence interval, 1.9-12.9). When participants were subdivided by gender, significantly increased ORs were seen only in women. CONCLUSIONS: In the oldest-old, high CRP levels are associated with increased odds of all-cause dementia, particularly in women. Prospective studies are necessary to confirm whether increased CRP levels are associated with an increased risk of developing dementia in this age group.
PMID: 19560102
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Cramer SC,Dobkin BH,Noser EA,Rodriguez RW,Enney LA
Department of Neurology, University of California, Irvine, USA. scramer@uci.edu
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Randomized, placebo-controlled, double-blind study of ropinirole in chronic stroke.
Stroke. 2009 Sep;40(9):3034-8
BACKGROUND AND PURPOSE: Evidence suggests the potential to improve motor status in patients with stroke by modifying brain catecholaminergic tone. The current study hypothesized that increased dopaminergic tone via the dopamine agonist ropinirole, when combined with physiotherapy (PT), would significantly and safely increase gait velocity. METHODS: Patients with moderate motor deficits due to stroke 1 to 12 months prior were randomized (double blinded) to 9 weeks of immediate-release ropinirole or placebo, each with PT, and followed up for 3 additional weeks. Drug dose (0.25 to 4 mg once daily) was titrated weekly, as tolerated. The primary end point was gait velocity during the 12 weeks of study participation. RESULTS: Patients in the ropinirole+PT group averaged 2.4 mg/d by end of week 9, although the target dose was at least 3 mg/d. Ropinirole+PT was generally safe and well tolerated, including no drug-related serious adverse events. Across all 33 enrollees, significant gains were found over time for gait velocity and for most secondary end points. However, gains did not differ by treatment assignment. PT and occupational therapy were commonly prescribed outside of the trial, although the extent of these was not correlated with study outcomes. CONCLUSIONS: At doses achieved in this trial, increased dopaminergic tone via ropinirole+PT was generally well tolerated but did not show any improvement over and above the effects of PT alone.
PMID: 19520987
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Ayala FJ
University of California, Irvine, CA 92697, USA. fjayala@uci.edu
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One hundred fifty years without Darwin are enough!
Genome Res. 2009 May;19(5):693-9
PMID: 19411593
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Felgner PL,Kayala MA,Vigil A,Burk C,Nakajima-Sasaki R,Pablo J,Molina DM,Hirst S,Chew JS,Wang D,Tan G,Duffield M,Yang R,Neel J,Chantratita N,Bancroft G,Lertmemongkolchai G,Davies DH,Baldi P,Peacock S,Titball RW
Department of Medicine, Division of Infectious Diseases, University of California, Irvine, CA 92697, USA. pfelgner@uci.edu
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A Burkholderia pseudomallei protein microarray reveals serodiagnostic and cross-reactive antigens.
Proc Natl Acad Sci U S A. 2009 Aug 11;106(32):13499-504
Understanding the way in which the immune system responds to infection is central to the development of vaccines and many diagnostics. To provide insight into this area, we fabricated a protein microarray containing 1,205 Burkholderia pseudomallei proteins, probed it with 88 melioidosis patient sera, and identified 170 reactive antigens. This subset of antigens was printed on a smaller array and probed with a collection of 747 individual sera derived from 10 patient groups including melioidosis patients from Northeast Thailand and Singapore, patients with different infections, healthy individuals from the USA, and from endemic and nonendemic regions of Thailand. We identified 49 antigens that are significantly more reactive in melioidosis patients than healthy people and patients with other types of bacterial infections. We also identified 59 cross-reactive antigens that are equally reactive among all groups, including healthy controls from the USA. Using these results we were able to devise a test that can classify melioidosis positive and negative individuals with sensitivity and specificity of 95% and 83%, respectively, a significant improvement over currently available diagnostic assays. Half of the reactive antigens contained a predicted signal peptide sequence and were classified as outer membrane, surface structures or secreted molecules, and an additional 20% were associated with pathogenicity, adaptation or chaperones. These results show that microarrays allow a more comprehensive analysis of the immune response on an antigen-specific, patient-specific, and population-specific basis, can identify serodiagnostic antigens, and contribute to a more detailed understanding of immunogenicity to this pathogen.
PMID: 19666533
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Romero Rosales K,Peralta ER,Guenther GG,Wong SY,Edinger AL
Department of Developmental and Cell Biology, University of California-Irvine, Irvine, CA 92697-2300, USA.
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Rab7 activation by growth factor withdrawal contributes to the induction of apoptosis.
Mol Biol Cell. 2009 Jun;20(12):2831-40
The Rab7 GTPase promotes membrane fusion reactions between late endosomes and lysosomes. In previous studies, we demonstrated that Rab7 inactivation blocks growth factor withdrawal-induced cell death. These results led us to hypothesize that growth factor withdrawal activates Rab7. Here, we show that growth factor deprivation increased both the fraction of Rab7 that was associated with cellular membranes and the percentage of Rab7 bound to guanosine triphosphate (GTP). Moreover, expressing a constitutively GTP-bound mutant of Rab7, Rab7-Q67L, was sufficient to trigger cell death even in the presence of growth factors. This activated Rab7 mutant was also able to reverse the growth factor-independent cell survival conferred by protein kinase C (PKC) delta inhibition. PKCdelta is one of the most highly induced proteins after growth factor withdrawal and contributes to the induction of apoptosis. To evaluate whether PKCdelta regulates Rab7, we first examined lysosomal morphology in cells with reduced PKCdelta activity. Consistent with a potential role as a Rab7 activator, blocking PKCdelta function caused profound lysosomal fragmentation comparable to that observed when Rab7 was directly inhibited. Interestingly, PKCdelta inhibition fragmented the lysosome without decreasing Rab7-GTP levels. Taken together, these results suggest that Rab7 activation by growth factor withdrawal contributes to the induction of apoptosis and that Rab7-dependent fusion reactions may be targeted by signaling pathways that limit growth factor-independent cell survival.
PMID: 19386765
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Astarita G,Ahmed F,Piomelli D
Department of Pharmacology, University of California - Irvine, Irvine, CA, USA.
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Lipidomic analysis of biological samples by liquid chromatography coupled to mass spectrometry.
Methods Mol Biol. 2009;579:201-19
Lipidomics studies the large-scale changes in nonwater-soluble metabolites (lipids) accompanying perturbations of biological systems. Because lipids are involved in crucial biological mechanisms, there is a growing scientific interest in using lipidomic approaches to understand the regulation of the lipid meta-bolism in all eukaryotic and prokaryotic organisms. Lipidomics is a powerful tool in system biology that can be used together with genomics, transcriptomics, and proteomics to answer biological questions arising from various scientific areas such as environmental sciences, pharmacology, nutrition, biophysics, cell biology, physiology, pathology, and disease diagnostics. One of the main challenges for lipidomic analysis is the range of concentrations and chemical complexity of different lipid species. In this chapter, we present a lipidomic approach that combines sample preparation, chromatographic, and intrasource ionization separation coupled to mass spectrometry for analyzing a broad-range of lipid molecules in biological samples.
PMID: 19763477
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Kawauchi S,Calof AL,Santos R,Lopez-Burks ME,Young CM,Hoang MP,Chua A,Lao T,Lechner MS,Daniel JA,Nussenzweig A,Kitzes L,Yokomori K,Hallgrimsson B,Lander AD
Department of Anatomy and Neurobiology, University of California Irvine, Irvine, California, United States of America.
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Multiple organ system defects and transcriptional dysregulation in the nipbl mouse, a model of cornelia de lange syndrome.
PLoS Genet. 2009 Sep;5(9):e1000650
Cornelia de Lange Syndrome (CdLS) is a multi-organ system birth defects disorder linked, in at least half of cases, to heterozygous mutations in the NIPBL gene. In animals and fungi, orthologs of NIPBL regulate cohesin, a complex of proteins that is essential for chromosome cohesion and is also implicated in DNA repair and transcriptional regulation. Mice heterozygous for a gene-trap mutation in Nipbl were produced and exhibited defects characteristic of CdLS, including small size, craniofacial anomalies, microbrachycephaly, heart defects, hearing abnormalities, delayed bone maturation, reduced body fat, behavioral disturbances, and high mortality (75-80%) during the first weeks of life. These phenotypes arose despite a decrease in Nipbl transcript levels of only approximately 30%, implying extreme sensitivity of development to small changes in Nipbl activity. Gene expression profiling demonstrated that Nipbl deficiency leads to modest but significant transcriptional dysregulation of many genes. Expression changes at the protocadherin beta (Pcdhb) locus, as well as at other loci, support the view that NIPBL influences long-range chromosomal regulatory interactions. In addition, evidence is presented that reduced expression of genes involved in adipogenic differentiation may underlie the low amounts of body fat observed both in Nipbl+/- mice and in individuals with CdLS.
PMID: 19763162
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Jeter PE,Dosher BA,Petrov A,Lu ZL
Memory Attention Perception (MAP) Laboratory, Department of Cognitive Sciences, UC Irvine, Irvine, CA, USA. pjeter@uci.edu.
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Task precision at transfer determines specificity of perceptual learning.
J Vis. 2009;9(3):1.1-13
Perceptual learning, the improvement in performance with practice, reflects plasticity in the adult visual system. We challenge a standard claim that specificity of perceptual learning depends on task difficulty during training, instead showing that specificity, or conversely transfer, is primarily controlled by the precision demands (i.e., orientation difference) of the transfer task. Thus, for an orientation discrimination task, transfer of performance improvement is observed in low-precision transfer tasks, while specificity of performance improvement is observed in high-precision transfer tasks, regardless of the precision of initial training. The nature of specificity places important constraints on mechanisms of transfer in visual learning. These results contribute to understanding generalization of practiced improvements that may be key to the development of expertise and for applications in remediation.
PMID: 19757940
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Saremi F,Knoll AN,Bendavid OJ,Schultze-Haakh H,Narula N,Sarlati F
Department of Radiological Sciences, Division of Body Imaging, University of California-Irvine, UCI Medical Center, 101 The City Drive, Route 140, Orange, CA 92868-3298, USA. fsaremi@uci.edu
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Characterization of genitourinary lesions with diffusion-weighted imaging.
Radiographics. 29(5):1295-317
Diffusion-weighted imaging has been widely accepted as a powerful imaging technique in neuroradiology. Until recently, the inclusion of diffusion-weighted sequences in body imaging protocols has been hindered by technical limitations. However, with advances in magnetic resonance (MR) imaging technology and technique, these limitations are being overcome. The addition of diffusion-weighted sequences to routine abdominopelvic MR imaging protocols has been found to yield diagnostically useful information with only a minimal increase in imaging time. More specifically, the use of diffusion-weighted imaging in the genitourinary system can facilitate the detection and characterization of genitourinary tract lesions that demonstrate equivocal signal intensity characteristics with routine MR imaging sequences. Diffusion-weighted imaging is not only helpful in differentiating benign from malignant processes, but it can also be used to assess meta-static lesions, possible tumor recurrence, and treatment response. Because it does not require injection of a gadolinium-based contrast agent, diffusion-weighted imaging can be used in patients with renal insufficiency or contrast material allergy. Most of the body diffusion-weighted imaging studies reported in the literature to date have been conducted with 1.5-T magnets. However, the feasibility of body diffusion-weighted imaging at 3.0 T is currently under investigation in an effort to determine the efficacy of the routine inclusion of diffusion-weighted imaging sequences in 3.0-T body MR imaging protocols.
PMID: 19755597
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Cahalan MD,Chandy KG
Department of Physiology and Biophysics, and the Institute for Immunology, University of California, Irvine, Irvine, CA 92697-4561, USA. mcahalan@uci.edu
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The functional network of ion channels in T lymphocytes.
Immunol Rev. 2009 Sep;231(1):59-87
For more than 25 years, it has been widely appreciated that Ca2+ influx is essential to trigger T-lymphocyte activation. Patch clamp analysis, molecular identification, and functional studies using blockers and genetic manipulation have shown that a unique contingent of ion channels orchestrates the initiation, intensity, and duration of the Ca2+ signal. Five distinct types of ion channels--Kv1.3, KCa3.1, Orai1+ stromal interacting molecule 1 (STIM1) [Ca2+-release activating Ca2+ (CRAC) channel], TRPM7, and Cl(swell)--comprise a network that performs functions vital for ongoing cellular homeostasis and for T-cell activation, offering potential targets for immunomodulation. Most recently, the roles of STIM1 and Orai1 have been revealed in triggering and forming the CRAC channel following T-cell receptor engagement. Kv1.3, KCa3.1, STIM1, and Orai1 have been found to cluster at the immunological synapse following contact with an antigen-presenting cell; we discuss how channels at the synapse might function to modulate local signaling. Immuno-imaging approaches are beginning to shed light on ion channel function in vivo. Importantly, the expression pattern of Ca2+ and K+ channels and hence the functional network can adapt depending upon the state of differentiation and activation, and this allows for different stages of an immune response to be targeted specifically.
PMID: 19754890
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Hoshino Y,Urakami T,Kodama T,Koide H,Oku N,Okahata Y,Shea KJ
Department of Chemistry, University of California, Irvine, Irvine, CA 92697, USA. yhoshino@uci.edu
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Design of synthetic polymer nanoparticles that capture and neutralize a toxic peptide.
Small. 2009 Jul;5(13):1562-8
Designed polymer nanoparticles (NPs) capable of binding and neutralizing a biomacromolecular toxin are prepared. A library of copolymer NPs is synthesized from combinations of functional monomers. The binding capacity and affinity of the NPs are individually analyzed. NPs with optimized composition are capable of neutralizing the toxin even in a complex biological milieu. It is anticipated that this strategy will be a starting point for the design of synthetic alternatives to antibodies.
PMID: 19296557
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Arold SP,Malavia N,George SC
Department of Biomedical Engineering, University of California, Irvine, USA. scgeorge@uci.edu
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Mechanical compression attenuates normal human bronchial epithelial wound healing.
Respir Res. 2009;10:9
BACKGROUND: Airway narrowing associated with chronic asthma results in the transmission of injurious compressive forces to the bronchial epithelium and promotes the release of pro-inflammatory mediators and the denudation of the bronchial epithelium. While the individual effects of compression or denudation are well characterized, there is no data to elucidate how these cells respond to the application of mechanical compression in the presence of a compromised epithelial layer. METHODS: Accordingly, differentiated normal human bronchial epithelial cells were exposed to one of four conditions: 1) unperturbed control cells, 2) single scrape wound only, 3) static compression (6 hours of 30 cmH2O), and 4) 6 hours of static compression after a scrape wound. Following treatment, wound closure rate was recorded, media was assayed for mediator content and the cytoskeletal network was fluorescently labeled. RESULTS: We found that mechanical compression and scrape injury increase TGF-beta2 and endothelin-1 secretion, while EGF content in the media is attenuated with both injury modes. The application of compression after a pre-existing scrape wound augmented these observations, and also decreased PGE2 media content. Compression stimulated depolymerization of the actin cytoskeleton and significantly attenuated wound healing. Closure rate was partially restored with the addition of exogenous PGE2, but not EGF. CONCLUSION: Our results suggest that mechanical compression reduces the capacity of the bronchial epithelium to close wounds, and is, in part, mediated by PGE2 and a compromised cytoskeleton.
PMID: 19171062
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