Odgers CL,Russell MA
Department of Psychology and Social Behavior, University of California, Irvine, 3361 Social Ecology, Bldg II, Irvine, CA 92697. codgers@uci.edu.
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Can Adolescent Dating Violence Be Prevented Through School-Based Programs?
Arch Pediatr Adolesc Med. 2009 Aug;163(8):767-768
PMID: 19652111
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Patel PM,Eisenberg J,Islam MA,Maree AO,Rosenfield KA
Division of Cardiology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. pranavp@uci.edu
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Percutaneous revascularization of persistent renal artery in-stent restenosis.
Vasc Med. 2009 Aug;14(3):259-64
Percutaneous renal artery stenting is a common means of treating atherosclerotic renal artery stenosis. However, renal artery restenosis remains a frequent problem. The optimal treatment of restenosis has not been established and may involve percutaneous renal artery angioplasty or deployment of a second stent. Other modalities include cutting balloon angioplasty, repeat stenting with drug-eluting stents or endovascular brachytherapy. Most recently, use of polytetrafluoroethylene (PTFE)-covered stents may offer a new and innovative way to treat recurrent renal artery stenosis. We describe a case in a patient who initially presented with renal insufficiency and multi-drug hypertension in the setting of severe bilateral renal artery stenosis. Her renal artery stenosis was initially successfully treated by percutaneous deployment of bilateral bare metal renal artery stents. After initial improvement of her hypertension and renal insufficiency, both parameters declined and follow-up duplex evaluation confirmed renal artery in-stent restenosis. Owing to other medical co-morbidities she was felt to be a poor surgical candidate and was subsequently treated first with bilateral cutting balloon angioplasty and second with drug-eluting stent deployment. Each procedure was associated with initial improvement of renal function and blood pressure control, which then later deteriorated with the development of further significant in-stent restenosis. It was then decided to treat the restenosis using PTFE-covered stents. At 12 months of follow-up, the blood pressure had remained stable and renal function had normalized. The covered stents remained free of any significant neointimal tissue or obstruction.
PMID: 19651676
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Floro JN,Dunton GE,Delfino RJ
Department of Psychology and Social Behavior, University of California-Irvine, CA 92612, USA.
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Assessing physical activity in children with asthma: convergent validity between accelerometer and electronic diary data.
Res Q Exerc Sport. 2009 Jun;80(2):153-63
Convergent validity of accelerometer and electronic diary physical activity data was assessed in children with asthma. Sixty-two participants, ages 9-18 years, wore an accelerometer and reported their physical activity level in quarter-hour segments every 2 hr using the Ambulatory Diary Assessment (ADA). Moderate validity was found between physical activity data from accelerometers and ADA (average individual participant Spearman r = .48, SD = 0.13). Within-participant accelerometer estimates for ADA sleep, rest, and light activity were different from each other and from higher activity (mixed model p < .0001), but moderate did not differ from strenuous activity (p = .70). Moderate validity between accelerometer and electronic diary data supports the use of ADA with short-term recall to capture gross changes in daily activity.
PMID: 19650380
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Sountoulides PG,Kaufmann OG,Kaplan AG,Louie MK,McDougall EM,Clayman RV
Urology Department, University of California, Irvine, CA, USA petross@uci.edu.
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Laparoscopic renal surgery.
Minerva Chir. 2009 Aug;64(4):373-94
Renal surgery, radical nephrectomy in particular, was historically the first application of laparoscopic techniques in urology. Since then, laparoscopy has been constantly evolving to claim its position in the surgical armamentarium of the urologist for the treatment of both malignant and benign diseases of the kidney and upper urinary tract. Over the years of increasing surgical experience and exposure, along with the evolution in the techniques and instruments used, laparoscopy has emerged as an equally effective and even more attractive alternative to open surgery for certain indications. The currently available load of literature is able to prove beyond any doubt the oncologic efficacy and minimal morbidity of laparoscopy for the treatment of renal masses in the form of radical or partial laparoscopic nephrectomy and nephroureterectomy. On the other hand, one can claim that laparoscopy is not far from replacing open surgery for the management of benign conditions such as ureteropelvic junction obstruction and donor nephrectomy. This review on laparoscopic renal surgery will discuss the major applications, indications, techniques and outcomes of laparoscopy in the contemporary management of benign and malignant renal diseases while focusing on its benefits and drawbacks compared to open surgery.
PMID: 19648858
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Garner CP,Murray JA,Ding YC,Tien Z,van Heel DA,Neuhausen SL
Department of Epidemiology, University of California Irvine, Irvine, CA USA.
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Replication of Celiac Disease UK Genome-Wide Association Study Results in a US Population.
Hum Mol Genet. 2009 Jul 31;:
Celiac disease is a common disease with a prevalence of approximately 1%. A recent genome-wide association study (GWAS) and follow-up study identified eight loci significantly associated with celiac disease risk. We genotyped the top 1020 non-HLA SNPs from the GWAS study that were genotyped in the previous follow-up study. After quality control assessments, 975 SNPs were analyzed for association with 906 celiac disease cases and 3819 controls, using logistic regression. Additional genotype data were generated by imputation and analyzed across the regions showing the strongest statistical evidence for association. Twenty SNPs were associated with celiac disease with p<0.01 in the current study as well as in the previous follow-up study, of which 16 had p< 0.001, and 11 had p<1 x10(-11). Five of the eight regions identified in the follow-up study were strongly associated with celiac disease, including regions on 1q31, 3q25, 3q28, 4q27, and 12q24. The strongest associations were at 4q27, the region most strongly associated in the GWAS and follow-up study and containing IL2 and IL21, and at 3q28 harboring LPP. In addition, we provide new evidence for an association, not previously reported, on 2q31 harboring a strong candidate gene, ITGA4. In conclusion, in this first follow-up study of celiac cases from the United States, we provide additional evidence that five of the eight previously identified regions harbor risk alleles for celiac disease, and new evidence for an association on 2q31. The underlying functional mutations responsible for these replicated associations need to be identified.
PMID: 19648293
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Duangdao DM,Clark SD,Okamura N,Reinscheid RK
Department of Pharmaceutical Sciences, University of California Irvine, Irvine, CA 92697, USA; Department of Molecular Biology & Biochemistry, University of California Irvine, Irvine, CA 92697, USA.
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Behavioral phenotyping of Neuroepeptide S receptor knockout mice.
Behav Brain Res. 2009 Jul 28;:
Central administration of Neuropeptide S (NPS) in rodents induces arousal and prolonged wakefulness as well as anxiolytic-like effects. NPS has also been implicated in modulation of cognitive functions and energy homeostasis. Here we present a comprehensive phenotypical analysis of mice carrying a targeted mutation in the NPS receptor (NPSR) gene. NPSR knockout mice were found to exhibit reduced exploratory activity when challenged with a novel environment, which might indicate attenuated arousal. We also observed attenuated late peak wheel running activity in NPSR knockout mice, representing reduced activity during the subjective evening. These mice also displayed increased anxiety-like behaviors when compared to their wildtype littermates, although analysis of anxiety behaviors was limited by genetic background influences. Unexpectedly, NPSR knockout mice showed enhanced motor performance skills. No phenotypical differences were detected in the forced-swim test, startle habituation and pre-pulse inhibition paradigms. Together, these data indicate that the endogenous NPS system might be involved in setting or maintaining behavioral arousal thresholds and that the NPS system might have other yet undiscovered physiological functions. (170 words).
PMID: 19646487
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Frieboes LR,Gupta R
University of California, Irvine, Biomedical Engineering, Irvine, California, United States; lrummler@uci.edu.
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An in vitro traumatic model to evaluate the response of myelinated cultures to sustained hydrostatic compression injury.
J Neurotrauma. 2009 Jul 31;:
While a variety of in vitro models have been employed to investigate the response of load-bearing tissues to hydrostatic pressure, long-term studies are limited by the need to provide for adequate gas exchange during pressurization. Applying compression in vitro may alter the equilibrium of the system and thereby disrupt the gas exchange kinetics. To address this, several sophisticated compression chamber designs have been developed. However, these systems are limited in the magnitude of pressure that can be applied and may require frequent media changes, thereby eliminating critical autocrine and paracrine signaling factors. To better isolate the cellular response to long-term compression, we created a model that features continuous gas flow through the chamber during pressurization and a negative feedback control system to rigorously control dissolved oxygen levels. Monitoring dissolved oxygen continuously during pressurization, we find that the ensuing response exhibits characteristics of a second- or higher-order system which can be mathematically modeled using a second-order differential equation. Finally, we use the system to model chronic nerve compression injuries, such as carpal tunnel syndrome and spinal nerve root stenosis, with myelinated neuron-Schwann cell co-cultures. Cell membrane integrity assay results show that co-cultures respond differently to hydrostatic pressure depending on the magnitude and duration of stimulation. In addition, we find that myelinated Schwann cells proliferate in response to applied hydrostatic compression.
PMID: 19645529
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Vilcins IM,Fournier PE,Old JM,Deane E
Department of Biological Sciences, E8A, Macquarie University, NSW 2109, Australia. ivilcins@uci.edu
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Evidence for the presence of Francisella and spotted fever group rickettsia DNA in the tick Amblyomma fimbriatum (Acari: Ixodidae), Northern Territory, Australia.
J Med Entomol. 2009 Jul;46(4):926-33
Ticks (n = 252) were collected from five wild-caught reptile species during routine trapping in the Djukbinj National Park and Fogg Dam Reserve, Northern Territory, Australia. Pooling of ticks (one to four ticks per pool), according to sex or host animal, resulted in 187 samples used for screening for the presence of Rickettsia species via molecular methods. Rickettsia DNA was detected via the amplification of the gltA, ompA, and ompB genes in 57 (34%) of the 187 tick samples, all of which contained only the tick Amblyomma fimbriatum Koch (Acari: Ixodidae). Further amplification and sequencing of nine of the positive samples (4.8%) for the gltA, ompA, ompB, 17-kDa, and 16S rRNA genes identified a Rickettsia species sharing closest identity to Rickettsia tamurae. In addition, amplification and sequencing of the 16S rRNA gene detected in the same tick samples the presence of a Francisella species closely related to other tick-borne Francisellae identified in ticks from the Northern Hemisphere.
PMID: 19645299
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Thornton KR
Department of Ecology and Evolutionary Biology, University of California Irvine, Irvine, CA, USA. krthornt@uci.edu
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Automating approximate Bayesian computation by local linear regression.
BMC Genet. 2009;10:35
BACKGROUND: In several biological contexts, parameter inference often relies on computationally-intensive techniques. "Approximate Bayesian Computation", or ABC, methods based on summary statistics have become increasingly popular. A particular flavor of ABC based on using a linear regression to approximate the posterior distribution of the parameters, conditional on the summary statistics, is computationally appealing, yet no standalone tool exists to automate the procedure. Here, I describe a program to implement the method. RESULTS: The software package ABCreg implements the local linear-regression approach to ABC. The advantages are: 1. The code is standalone, and fully-documented. 2. The program will automatically process multiple data sets, and create unique output files for each (which may be processed immediately in R), facilitating the testing of inference procedures on simulated data, or the analysis of multiple data sets. 3. The program implements two different transformation methods for the regression step. 4. Analysis options are controlled on the command line by the user, and the program is designed to output warnings for cases where the regression fails. 5. The program does not depend on any particular simulation machinery (coalescent, forward-time, etc.), and therefore is a general tool for processing the results from any simulation. 6. The code is open-source, and modular.Examples of applying the software to empirical data from Drosophila melanogaster, and testing the procedure on simulated data, are shown. CONCLUSION: In practice, the ABCreg simplifies implementing ABC based on local-linear regression.
PMID: 19583871
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Michalewski HJ,Starr A,Zeng FG,Dimitrijevic A
Department of Neurology, Med. Surge I, Room 150, University of California, Irvine, CA 92697-4290, USA. hjmichal@uci.edu
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N100 cortical potentials accompanying disrupted auditory nerve activity in auditory neuropathy (AN): effects of signal intensity and continuous noise.
Clin Neurophysiol. 2009 Jul;120(7):1352-63
OBJECTIVE: Auditory temporal processes in quiet are impaired in auditory neuropathy (AN) similar to normal hearing subjects tested in noise. N100 latencies were measured from AN subjects at several tone intensities in quiet and noise for comparison with a group of normal hearing individuals. METHODS: Subjects were tested with brief 100 ms tones (1.0 kHz, 100-40 dB SPL) in quiet and in continuous noise (90 dB SPL). N100 latency and amplitude were analyzed as a function of signal intensity and audibility. RESULTS: N100 latency in AN in quiet was delayed and amplitude was reduced compared to the normal group; the extent of latency delay was related to psychoacoustic measures of gap detection threshold and speech recognition scores, but not to audibility. Noise in normal hearing subjects was accompanied by N100 latency delays and amplitude reductions paralleling those found in AN tested in quiet. Additional N100 latency delays and amplitude reductions occurred in AN with noise. CONCLUSIONS: N100 latency to tones and performance on auditory temporal tasks were related in AN subjects. Noise masking in normal hearing subjects affected N100 latency to resemble AN in quiet. SIGNIFICANCE: N100 latency to tones may serve as an objective measure of the efficiency of auditory temporal processes.
PMID: 19535287
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Owerkowicz T,Elsey RM,Hicks JW
Ecology and Evolutionary Biology, University of California, Irvine, CA 92697, USA. towerkow@uci.edu
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Atmospheric oxygen level affects growth trajectory, cardiopulmonary allometry and metabolic rate in the American alligator (Alligator mississippiensis).
J Exp Biol. 2009 May;212(Pt 9):1237-47
Recent palaeoatmospheric models suggest large-scale fluctuations in ambient oxygen level over the past 550 million years. To better understand how global hypoxia and hyperoxia might have affected the growth and physiology of contemporary vertebrates, we incubated eggs and raised hatchlings of the American alligator. Crocodilians are one of few vertebrate taxa that survived these global changes with distinctly conservative morphology. We maintained animals at 30 degrees C under chronic hypoxia (12% O(2)), normoxia (21% O(2)) or hyperoxia (30% O(2)). At hatching, hypoxic animals were significantly smaller than their normoxic and hyperoxic siblings. Over the course of 3 months, post-hatching growth was fastest under hyperoxia and slowest under hypoxia. Hypoxia, but not hyperoxia, caused distinct scaling of major visceral organs-reduction of liver mass, enlargement of the heart and accelerated growth of lungs. When absorptive and post-absorptive metabolic rates were measured in juvenile alligators, the increase in oxygen consumption rate due to digestion/absorption of food was greatest in hyperoxic alligators and smallest in hypoxic ones. Hyperoxic alligators exhibited the lowest breathing rate and highest oxygen consumption per breath. We suggest that, despite compensatory cardiopulmonary remodelling, growth of hypoxic alligators is constrained by low atmospheric oxygen supply, which may limit their food utilisation capacity. Conversely, the combination of elevated metabolism and low cost of breathing in hyperoxic alligators allows for a greater proportion of metabolised energy to be available for growth. This suggests that growth and metabolic patterns of extinct vertebrates would have been significantly affected by changes in the atmospheric oxygen level.
PMID: 19376944
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Edwards RA,Witherspoon M,Wang K,Afrasiabi K,Pham T,Birnbaumer L,Lipkin SM
Department of Pathology, University of California-Irvine, Irvine, California 92697-4800, USA. redwards@uci.edu
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Epigenetic repression of DNA mismatch repair by inflammation and hypoxia in inflammatory bowel disease-associated colorectal cancer.
Cancer Res. 2009 Aug 15;69(16):6423-9
Sporadic human mismatch repair (MMR)-deficient colorectal cancers account for approximately 12.5% of all cases of colorectal cancer. MMR-deficient colorectal cancers are classically characterized by right-sided location, multifocality, mucinous histology, and lymphocytic infiltration. However, tumors in germ-line MMR-deficient mouse models lack these histopathologic features. Mice lacking the heterotrimeric G protein alpha subunit Gialpha2 develop chronic colitis and multifocal, right-sided cancers with mucinous histopathology, similar to human MMR-deficient colorectal cancer. Young Gialpha2-/- colonic epithelium has normal MMR expression but selectively loses MLH1 and consequently PMS2 expression following inflammation. Gialpha2-/- cancers have microsatellite instability. Mlh1 is epigenetically silenced not by promoter hypermethylation but by decreased histone acetylation. Chronically inflamed Gialpha2-/- colonic mucosa contains patchy hypoxia, with increased crypt expression of the hypoxia markers DEC-1 and BNIP3. Chromatin immunoprecipitation identified increased binding of the transcriptional repressor DEC-1 to the proximal Mlh1 promoter in hypoxic YAMC cells and colitic Gialpha2-/- crypts. Treating Gialpha2-/- mice with the histone deacetylase inhibitor suberoylanilide hydroxamic acid significantly decreased colitis activity and rescued MLH1 expression in crypt epithelial cells, which was associated with increased acetyl histone H3 levels and decreased DEC-1 binding at the proximal Mlh1 promoter, consistent with a histone deacetylase-dependent mechanism. These data link chronic hypoxic inflammation, epigenetic MMR protein down-regulation, development of MMR-deficient colorectal cancer, and the firstmouse model of somatically acquired MMR-deficient colorectal cancer.
PMID: 19638594
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Jones NF,Schneeberger S
Department of Orthopedic Surgery and Division of Plastic Surgery, University of California, Irvine, California, USA. nfjones@uci.edu
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Arm transplantation: prospects and visions.
Transplant Proc. 2009 Mar;41(2):476-80
Based on the results of above-elbow replantation, it is possible that above-elbow arm transplantation will be successful and result in a superior functional outcome as defined by the Chen criteria. Above-elbow arm transplantation is probably technically simpler than distal forearm or wrist transplantation, especially since the macroanastomoses do not require microsurgical expertise. However, hand function depends on reinnervation of forearm muscles and the distance for nerves to regenerate for reinnervation of intrinsic muscles of the hand is significant. The vascularized bone marrow transplanted with the arm holds potential to induce chimerism and promote tolerance but could also make the recipient more susceptible to graft-versus-host disease. Prospective trials comparing the functional results after above-elbow arm transplantation with the functional results achieved by the best neuronal-controlled above-elbow prosthesis are warranted and will determine the gold standard of upper-extremity reconstruction.
PMID: 19328907
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Binder DK,Podlogar M,Clusmann H,Bien C,Urbach H,Schramm J,Kral T
Department of Neurological Surgery, University of California, Irvine, California, USA. dbinder@uci.edu
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Surgical treatment of parietal lobe epilepsy.
J Neurosurg. 2009 Jun;110(6):1170-8
OBJECT: Parietal lobe epilepsy (PLE) accounts for a small percentage of extratemporal epilepsies, and only a few and mostly smaller series have been reported. Preoperative findings, surgical strategies, pathological bases, and postoperative outcomes for PLE remain to be elucidated.METHODS: Patients with PLE were identified by screening a prospective epilepsy surgery database established in 1989 at the University of Bonn. Charts, preoperative imaging studies, surgical reports, and neuropathological findings were reviewed. Seizure outcome was classified according to Engel class (I-IV).RESULTS: Forty patients (23 females and 17 males) with PLE were identified and had a mean age of 25.0 years and a mean preoperative epilepsy duration of 13.7 years. Nine patients had a significant medical history (for example, trauma, meningitis/encephalitis, or perinatal hypoxia). Preoperative MR imaging abnormalities were identified in 38 (95%) of 40 patients; 26 patients (65%) underwent invasive electroencephalography evaluation. After lesionectomy of the dominant (in 20 patients) or nondominant (in 20 patients) parietal lobe and additional multiple subpial transections (in 11 patients), 2 patients suffered from surgical and 12 from neurological complications, including temporary partial Gerstmann syndrome. There were no deaths. Histopathological analysis revealed 16 low-grade tumors, 11 cortical dysplasias, 9 gliotic scars, 2 cavernous vascular malformations, and 1 granulomatous inflammation. In 1 case, no histopathological diagnosis could be made. After a mean follow-up of 45 months, 27 patients (67.5%) became seizure free or had rare seizures (57.5% Engel Class I; 10% Engel Class II; 27.5% Engel Class III; and 5% Engel Class IV).CONCLUSIONS: Parietal lobe epilepsy is an infrequent cause of extratemporal epilepsy. Satisfactory results (Engel Classes I and II) were obtained in 67.5% of patients in our series. A temporary partial hemisensory or Gerstmann syndrome occurs in a significant number of patients.
PMID: 19199502
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Sevrioukova IF
Department of Molecular Biology and Biochemistry, University of California, Irvine, 92697-3900, USA. sevrioui@uci.edu
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Redox-linked conformational dynamics in apoptosis-inducing factor.
J Mol Biol. 2009 Jul 31;390(5):924-38
Apoptosis-inducing factor (AIF) is a bifunctional mitochondrial flavoprotein critical for energy metabolism and induction of caspase-independent apoptosis, whose exact role in normal mitochondria remains unknown. Upon reduction with NADH, AIF undergoes dimerization and forms tight, long-lived FADH(2)-NAD charge-transfer complexes (CTC) that are proposed to be functionally important. To obtain a deeper insight into structure/function relations and redox mechanism of this vitally important protein, we determined the X-ray structures of oxidized and NADH-reduced forms of naturally folded recombinant murine AIF. Our structures reveal that CTC with the pyridine nucleotide is stabilized by (i) pi-stacking interactions between coplanar nicotinamide, isoalloxazine, and Phe309 rings; (ii) rearrangement of multiple aromatic residues in the C-terminal domain, likely serving as an electron delocalization site; and (iii) an extensive hydrogen-bonding network involving His453, a key residue that undergoes a conformational switch to directly interact with and optimally orient the nicotinamide for charge transfer. Via the His453-containing peptide, redox changes in the active site are transmitted to the surface, promoting AIF dimerization and restricting access to a primary nuclear localization signal through which the apoptogenic form is transported to the nucleus. Structural findings agree with biochemical data and support the hypothesis that both normal and apoptogenic functions of AIF are controlled by NADH.
PMID: 19447115
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Vilcins IM,Old JM,Deane E
Department of Biological Sciences, E8A, Macquarie University, NSW, 2109, Australia. ivilcins@uci.edu.au
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Detection of a Hepatozoon and spotted fever group Rickettsia species in the common marsupial tick (Ixodes tasmani) collected from wild Tasmanian devils (Sarcophilus harrisii), Tasmania.
Vet Parasitol. 2009 May 26;162(1-2):23-31
Tasmanian devils are the largest extant marsupial carnivores, confined to the Australian island state of Tasmania. The iconic marsupial has dramatically declined in number since the discovery of devil facial tumor disease in 1996 and efforts are being made to uncover vital information to assist in the long-term survival of the species. Ticks are the main vectors of arthropod-borne disease in animals, raising the question of whether Tasmanian devils may be host to arthropods capable of harboring infectious agents. Partially engorged ticks were collected from 35 wild Tasmanian devils and tested for the presence of a range of tick-borne genera. A spotted fever group Rickettsia was detected in 45.5% of samples of the tick Ixodes tasmani (n=44), from all trapping locations, sharing close sequence identity to members of the Rickettsia massiliae group. A Hepatozoon species was also identified in 34.1% of the same sample set, sharing sequence similarities to Hepatozoon felis, a known pathogen of felids. Dual detection was identified in 13.6% of tick samples, where prevalence of the two genera overlapped. The existence of two previously undetected species of genera known for containing pathogens identifies additional potential risks to the health of the devil population.
PMID: 19303711
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Hipp JR,Jannetta J,Shah R,Turner S
Department of Criminology, Law and Society, University of California, Irvine, CA 92697, USA. john.hipp@UCI.edu
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Parolees' physical closeness to health service providers: a study of California parolees.
Health Place. 2009 Sep;15(3):649-58
We studied a sample of parolees and health service providers in the state of California in 2005-2006 to examine the relative physical closeness to health providers (and the potential demand of these providers) of parolees based on their demographic and prior offending characteristics. Although African-American and Latino parolees have more health providers nearby, these providers have considerably more potential demand. The health providers near long-term prisoners and sex offenders have more potential demand. The results suggest inequity in access to services, as minority parolees and those with greater needs may live near more impacted providers. The results also suggest some differences in access based on rural, suburban, or urban location.
PMID: 19119053
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Penner AM
Department of Sociology, University of California, Irvine, California 92697-5100, USA. andrew.penner@uci.edu
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Gender differences in extreme mathematical achievement: an international perspective on biological and social factors.
AJS. 2008;114 Suppl:S138-70
Genetic and other biological explanations have reemerged in recent scholarship on the underrepresentation of women in mathematics and the sciences. This study engages this debate by using international data-including math achievement scores from the Third International Mathematics and Sciences Study and country-level data from the World Bank, the United Nations, the International Labour Organization, the World Values Survey, and the International Social Survey Programme-to demonstrate the importance of social factors and to estimate an upper bound for the impact of genetic factors. The author argues that international variation provides a valuable opportunity to present simple and powerful arguments for the continued importance of social factors. In addition, where previous research has, by and large, focused on differences in population means, this work examines gender differences throughout the distribution. The article shows that there is considerable variation in gender differences internationally, a finding not easily explained by strictly biological theories. Modeling the cross-national variation in gender differences with country-level predictors reveals that differences among high achievers are related to gender inequality in the labor market and differences in the overall status of men and women.
PMID: 19569403
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Potkin SG,Turner JA,Guffanti G,Lakatos A,Torri F,Keator DB,Macciardi F
Department of Psychiatry and Human Behavior, University California of Irvine, Irvine, CA, USA. sgpotkin@uci.edu
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Genome-wide strategies for discovering genetic influences on cognition and cognitive disorders: methodological considerations.
Cogn Neuropsychiatry. 2009;14(4-5):391-418
INTRODUCTION: Genes play a well-documented role in determining normal cognitive function. This paper focuses on reviewing strategies for the identification of common genetic variation in genes that modulate normal and abnormal cognition with a genome-wide association scan (GWAS). GWASs make it possible to survey the entire genome to discover important but unanticipated genetic influences. METHODS: The use of a quantitative phenotype in combination with a GWAS provides many advantages over a case-control design, both in power and in physiological understanding of the underlying cognitive processes. We review the major features of this approach, and show how, using a General Linear Model method, the contribution of each Single Nucleotide Polymorphism (SNP) to the phenotype is determined, and adjustments then made for multiple tests. An example of the strategy is presented, in which fMRI measures of cortical inefficiency while performing a working memory task are used as the quantitative phenotype. We estimate power under different effect sizes (10-30%) and variations in allelic frequency for a Quantitative Trait (QT) (10-20%), and compare them to a case-control design with an Odds Ratio (OR) of 1.5, showing how a QT approach is superior to a traditional case-control. In the presented example, this method identifies putative susceptibility genes for schizophrenia which affect prefrontal efficiency and have functions related to cell migration, forebrain development and stress response. CONCLUSION: The use of QT as phenotypes provide increased statistical power over categorical association approaches and when combined with a GWAS creates a strategy for identification of unanticipated genes that modulate cognitive processes and cognitive disorders.
PMID: 19634037
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Amin A
Department of Medicine, University of California-Irvine, 101 The City Drive, Orange, CA 92868, USA. anamin@uci.edu
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Clinical and economic consequences of ventilator-associated pneumonia.
Clin Infect Dis. 2009 Aug 15;49 Suppl 1:S36-43
Increasing drug resistance rates among gram-negative pathogens that frequently cause ventilator-associated pneumonia have resulted in increased hospital mortality, longer hospital stays, and higher inpatient health care costs. There is an urgent need for effective therapies that lessen the clinical and economic consequences of this nosocomial infection. In a randomized, multicenter, prospective, phase 3 trial, medical resource use associated with doripenem was compared with that associated with imipenem for the treatment of ventilator-associated pneumonia. Analysis of medical resource use revealed that patients who received doripenem had a significantly shorter duration of hospital stay (22 vs. 27 days; P = .01)and duration of mechanical ventilation use (7 vs. 10 days; P = .03) than did patients who received imipenem. In addition, the duration of intensive care unit stay tended to be shorter for patients who received doripenem. The reduced medical resource use achieved with use of doripenem for treatment of ventilator-associated pneumonia may provide not only clinical benefits to patients but also economic benefits to hospitals and health care systems.
PMID: 19619020
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Arce L,Pate KT,Waterman ML
Department of Microbiology and Molecular Genetics, University of California Irvine, Irvine, CA 92697-4025, USA. larce@coh.org
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Groucho binds two conserved regions of LEF-1 for HDAC-dependent repression.
BMC Cancer. 2009;9:159
BACKGROUND: Drosophila Groucho and its human Transducin-like-Enhancer of Split orthologs (TLEs) function as transcription co-repressors within the context of Wnt signaling, a pathway with strong links to cancer. The current model for how Groucho/TLE's modify Wnt signaling is by direct competition with beta-catenin for LEF/TCF binding. The molecular events involved in this competitive interaction are not defined and the actions of Groucho/TLEs within the context of Wnt-linked cancer are unknown. METHODS: We used in vitro protein interaction assays with the LEF/TCF family member LEF-1, and in vivo assays with Wnt reporter plasmids to define Groucho/TLE interaction and repressor function. RESULTS: Mapping studies reveal that Groucho/TLE binds two regions in LEF-1. The primary site of recognition is a 20 amino acid region in the Context Dependent Regulatory domain. An auxiliary site is in the High Mobility Group DNA binding domain. Mutation of an eight amino acid sequence within the primary region (RFSHHMIP) results in a loss of Groucho action in a transient reporter assay. Drosophila Groucho, human TLE-1, and a truncated human TLE isoform Amino-enhancer-of-split (AES), work equivalently to repress LEF-1*beta-catenin transcription in transient reporter assays, and these actions are sensitive to the HDAC inhibitor Trichostatin A. A survey of Groucho/TLE action in a panel of six colon cancer cell lines with elevated beta-catenin shows that Groucho is not able to repress transcription in a subset of these cell lines. CONCLUSION: Our data shows that Groucho/TLE repression requires two sites of interaction in LEF-1 and that a central, conserved amino acid sequence within the primary region (F S/T/P/xx y I/L/V) is critical. Our data also reveals that AES opposes LEF-1 transcription activation and that both Groucho and AES repression require histone deacetylase activity suggesting multiple steps in Groucho competition with beta-catenin. The variable ability of Groucho/TLE to oppose Wnt signaling in colon cancer cells suggests there may be defects in one or more of these steps.
PMID: 19460168
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Lin KK,Kumar V,Geyfman M,Chudova D,Ihler AT,Smyth P,Paus R,Takahashi JS,Andersen B
Department of Biological Chemistry, University of California Irvine, Irvine, California, United States of America.
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Circadian clock genes contribute to the regulation of hair follicle cycling.
PLoS Genet. 2009 Jul;5(7):e1000573
Hair follicles undergo recurrent cycling of controlled growth (anagen), regression (catagen), and relative quiescence (telogen) with a defined periodicity. Taking a genomics approach to study gene expression during synchronized mouse hair follicle cycling, we discovered that, in addition to circadian fluctuation, CLOCK-regulated genes are also modulated in phase with the hair growth cycle. During telogen and early anagen, circadian clock genes are prominently expressed in the secondary hair germ, which contains precursor cells for the growing follicle. Analysis of Clock and Bmal1 mutant mice reveals a delay in anagen progression, and the secondary hair germ cells show decreased levels of phosphorylated Rb and lack mitotic cells, suggesting that circadian clock genes regulate anagen progression via their effect on the cell cycle. Consistent with a block at the G1 phase of the cell cycle, we show a significant upregulation of p21 in Bmal1 mutant skin. While circadian clock mechanisms have been implicated in a variety of diurnal biological processes, our findings indicate that circadian clock genes may be utilized to modulate the progression of non-diurnal cyclic processes.
PMID: 19629164
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Butts CT
Department of Sociology and Institute for Mathematical Behavioral Sciences, University of California at Irvine, 3151 Social Science Plaza, Irvine, CA 92697-5100, USA. buttsc@uci.edu
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Revisiting the foundations of network analysis.
Science. 2009 Jul 24;325(5939):414-6
Network analysis has emerged as a powerful way of studying phenomena as diverse as interpersonal interaction, connections among neurons, and the structure of the Internet. Appropriate use of network analysis depends, however, on choosing the right network representation for the problem at hand.
PMID: 19628855
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Dean MN,Mull CG,Gorb SN,Summers AP
Ecology and Evolutionary Biology, University of California Irvine, Irvine CA, USA.
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Ontogeny of the tessellated skeleton: insight from the skeletal growth of the round stingray Urobatis halleri.
J Anat. 2009 Jul 15;:
Abstract The majority of the skeleton of elasmobranch fishes (sharks, rays and relatives) is tessellated: uncalcified cartilage is overlain by a superficial rind of abutting, mineralized, hexagonal blocks called tesserae. We employed a diversity of imaging techniques on an ontogenetic series of jaw samples to investigate the development of the tessellated skeleton in a stingray (Urobatis halleri). We compared these data with the cellular changes that characterize cartilage calcification in bony skeletons. Skeletal growth is characterized by the appearance of tesserae as well as changes in chondrocyte shape, arrangement and density. Yolk sac embryos (35-56 mm disc width, DW) have untessellated lower jaw tissue wrapped in perichondrium and densely packed with chondrocytes. Chondrocyte density decreases dramatically after yolk sac absorption (histotroph stage: 57-80 mm DW) until the formation of tesserae, which are first visible using our techniques as thin (~60 microm), sub-perichondral plaques. During the histotroph stage, flattened chondrocytes align parallel to the perichondrium at the tissue periphery, where we believe they are incorporated into developing tesserae to form the cell-rich laminae observed within tesserae; in older animals peripheral cells in the uncalcified phase are rounder and less uniformly oriented. By parturition (~75 mm DW), cell density and the number of adjoining chondrocyte pairs (an indicator of cell division) have dropped to less than a third of their initial values; these remain low and tesserae continue to grow in size. The tessellated skeleton is a simple solution to the conundrum of growth in an endoskeleton with external mineralization and no remodeling. Although we see parallels with endochondral ossification (e.g. chondrocytes decreasing in density with age), the lack of chondrocyte hypertrophy and the fact that mineralization is sub-perichondral (not the case in mammalian cartilage) suggest that the similarities end there.
PMID: 19627389
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Dasgupta G,Chentoufi AA,Nesburn AB,Wechsler SL,BenMohamed L
The Gavin S Herbert Eye Institute, Cellular and Molecular Immunology Laboratory, Department of Ophthalmology, University of California, Irvine, College of Medicine, Irvine, CA 92697-4375, USA. gdasgupt@uci.edu
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New concepts in herpes simplex virus vaccine development: notes from the battlefield.
Expert Rev Vaccines. 2009 Aug;8(8):1023-35
The recent discovery that T cells recognize different sets of herpes simplex virus type 1 and type 2 epitopes from seropositive symptomatic and asymptomatic individuals might lead to a fundamental immunologic advance in vaccine development against herpes infection and diseases. The newly introduced needle-free mucosal (i.e., topical ocular and intravaginal) lipopeptide vaccines provide a novel strategy that might target ocular and genital herpes and possibly provide 'heterologous protection' from HIV-1. Indeed, mucosal self-adjuvanting lipopeptide vaccines are easy to manufacture, simple to characterize, extremely pure, cost-effective, highly immunogenic and safe. In this review, we bring together recent published and unpublished data that illuminates the status of epitope-based herpes vaccine development and present an overview of our recent approach to an 'asymptomatic epitope'-based lipopeptide vaccine.
PMID: 19627185
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