Showing papers by "University of Southern California published in 2000"

Comparison of Upper Gastrointestinal Toxicity of Rofecoxib and Naproxen in Patients with Rheumatoid Arthritis

Abstract: Background Each year, clinical upper gastrointestinal events occur in 2 to 4 percent of patients who are taking nonselective nonsteroidal antiinflammatory drugs (NSAIDs). We assessed whether rofecoxib, a selective inhibitor of cyclooxygenase-2, would be associated with a lower incidence of clinically important upper gastrointestinal events than is the nonselective NSAID naproxen among patients with rheumatoid arthritis. Methods We randomly assigned 8076 patients who were at least 50 years of age (or at least 40 years of age and receiving long-term glucocorticoid therapy) and who had rheumatoid arthritis to receive either 50 mg of rofecoxib daily or 500 mg of naproxen twice daily. The primary end point was confirmed clinical upper gastrointestinal events (gastroduodenal perforation or obstruction, upper gastrointestinal bleeding, and symptomatic gastroduodenal ulcers). Results Rofecoxib and naproxen had similar efficacy against rheumatoid arthritis. During a median follow-up of 9.0 months, 2.1 confirmed ga...

GPS-less low-cost outdoor localization for very small devices

Abstract: Instrumenting the physical world through large networks of wireless sensor nodes, particularly for applications like environmental monitoring of water and soil, requires that these nodes be very small, lightweight, untethered, and unobtrusive. The problem of localization, that is, determining where a given node is physically located in a network, is a challenging one, and yet extremely crucial for many of these applications. Practical considerations such as the small size, form factor, cost and power constraints of nodes preclude the reliance on GPS of all nodes in these networks. We review localization techniques and evaluate the effectiveness of a very simple connectivity metric method for localization in outdoor environments that makes use of the inherent RF communications capabilities of these devices. A fixed number of reference points in the network with overlapping regions of coverage transmit periodic beacon signals. Nodes use a simple connectivity metric, which is more robust to environmental vagaries, to infer proximity to a given subset of these reference points. Nodes localize themselves to the centroid of their proximate reference points. The accuracy of localization is then dependent on the separation distance between two-adjacent reference points and the transmission range of these reference points. Initial experimental results show that the accuracy for 90 percent of our data points is within one-third of the separation distance. However, future work is needed to extend the technique to more cluttered environments.

Ultra-wide bandwidth time-hopping spread-spectrum impulse radio for wireless multiple-access communications

Abstract: Attractive features of time-hopping spread-spectrum multiple-access systems employing impulse signal technology are outlined, and emerging design issues are described. Performance of such communications systems in terms of achievable transmission rate and multiple-access capability are estimated for both analog and digital data modulation formats under ideal multiple-access channel conditions.

A classification and comparison framework for software architecture description languages

Abstract: Software architectures shift the focus of developers from lines-of-code to coarser-grained architectural elements and their overall interconnection structure. Architecture description languages (ADLs) have been proposed as modeling notations to support architecture-based development. There is, however, little consensus in the research community on what is an ADL, what aspects of an architecture should be modeled in an ADL, and which of several possible ADLs is best suited for a particular problem. Furthermore, the distinction is rarely made between ADLs on one hand and formal specification, module interconnection, simulation and programming languages on the other. This paper attempts to provide an answer to these questions. It motivates and presents a definition and a classification framework for ADLs. The utility of the definition is demonstrated by using it to differentiate ADLs from other modeling notations. The framework is used to classify and compare several existing ADLs, enabling us, in the process, to identify key properties of ADLs. The comparison highlights areas where existing ADLs provide extensive support and those in which they are deficient, suggesting a research agenda for the future.

High-efficiency fluorescent organic light-emitting devices using a phosphorescent sensitizer

Abstract: To obtain the maximum luminous efficiency from an organic material, it is necessary to harness both the spin-symmetric and anti-symmetric molecular excitations (bound electron-hole pairs, or excitons) that result from electrical pumping This is possible if the material is phosphorescent, and high efficiencies have been observed in phosphorescent organic light-emitting devices However, phosphorescence in organic molecules is rare at room temperature The alternative radiative process of fluorescence is more common, but it is approximately 75% less efficient, due to the requirement of spin-symmetry conservation Here, we demonstrate that this deficiency can be overcome by using a phosphorescent sensitizer to excite a fluorescent dye The mechanism for energetic coupling between phosphorescent and fluorescent molecular species is a long-range, non-radiative energy transfer: the internal efficiency of fluorescence can be as high as 100% As an example, we use this approach to nearly quadruple the efficiency of a fluorescent red organic light-emitting device

Interval type-2 fuzzy logic systems: theory and design

Abstract: We present the theory and design of interval type-2 fuzzy logic systems (FLSs). We propose an efficient and simplified method to compute the input and antecedent operations for interval type-2 FLSs: one that is based on a general inference formula for them. We introduce the concept of upper and lower membership functions (MFs) and illustrate our efficient inference method for the case of Gaussian primary MFs. We also propose a method for designing an interval type-2 FLS in which we tune its parameters. Finally, we design type-2 FLSs to perform time-series forecasting when a nonstationary time-series is corrupted by additive noise where SNR is uncertain and demonstrate an improved performance over type-1 FLSs.

MethyLight: a high-throughput assay to measure DNA methylation

Abstract: Cytosine-5 DNA methylation occurs in the context of CpG dinucleotides in vertebrates. Aberrant methylation of CpG islands in human tumors has been shown to cause transcriptional silencing of tumor-suppressor genes. Most methods used to analyze cytosine-5 methylation patterns require cumbersome manual techniques that employ gel electrophoresis, restriction enzyme digestion, radiolabeled dNTPs or hybridization probes. The development of high-throughput technology for the analysis of DNA methylation would significantly expand our ability to derive molecular information from clinical specimens. This study describes a high-throughput quantitative methylation assay that utilizes fluorescence-based real-time PCR (TaqMan®) technology that requires no further manipulations after the PCR step. MethyLight is a highly sensitive assay, capable of detecting methylated alleles in the presence of a 10 000-fold excess of unmethylated alleles. The assay is also highly quantitative and can very accurately determine the relative prevalence of a particular pattern of DNA methylation. We show that MethyLight can distinguish between mono-allelic and bi-allelic methylation of the MLH1 mismatch repair gene in human colorectal tumor specimens. The development of this technique should considerably enhance our ability to rapidly and accurately generate epigenetic profiles of tumor samples.

Fate of the mammalian cranial neural crest during tooth and mandibular morphogenesis

Abstract: Neural crest cells are multipotential stem cells that contribute extensively to vertebrate development and give rise to various cell and tissue types. Determination of the fate of mammalian neural crest has been inhibited by the lack of appropriate markers. Here, we make use of a two-component genetic system for indelibly marking the progeny of the cranial neural crest during tooth and mandible development. In the first mouse line, Cre recombinase is expressed under the control of the Wnt1 promoter as a transgene. Significantly, Wnt1 transgene expression is limited to the migrating neural crest cells that are derived from the dorsal CNS. The second mouse line, the ROSA26 conditional reporter (R26R), serves as a substrate for the Cre-mediated recombination. Using this two-component genetic system, we have systematically followed the migration and differentiation of the cranial neural crest (CNC) cells from E9.5 to 6 weeks after birth. Our results demonstrate, for the first time, that CNC cells contribute to the formation of condensed dental mesenchyme, dental papilla, odontoblasts, dentine matrix, pulp, cementum, periodontal ligaments, chondrocytes in Meckel's cartilage, mandible, the articulating disc of temporomandibular joint and branchial arch nerve ganglia. More importantly, there is a dynamic distribution of CNC- and non-CNC-derived cells during tooth and mandibular morphogenesis. These results are a first step towards a comprehensive understanding of neural crest cell migration and differentiation during mammalian craniofacial development. Furthermore, this transgenic model also provides a new tool for cell lineage analysis and genetic manipulation of neural-crest-derived components in normal and abnormal embryogenesis.

Clearance of Alzheimer's amyloid-ss(1-40) peptide from brain by LDL receptor-related protein-1 at the blood-brain barrier.

Abstract: Elimination of amyloid-ss peptide (Ass) from the brain is poorly understood. After intracerebral microinjections in young mice, (125)I-Ass(1-40) was rapidly removed from the brain (t(1/2)

Prognostic factors in colorectal cancer. College of American Pathologists Consensus Statement 1999.

Abstract: Background Under the auspices of the College of American Pathologists, the current state of knowledge regarding pathologic prognostic factors (factors linked to outcome) and predictive factors (factors predicting response to therapy) in colorectal carcinoma was evaluated. A multidisciplinary group of clinical (including the disciplines of medical oncology, surgical oncology, and radiation oncology), pathologic, and statistical experts in colorectal cancer reviewed all relevant medical literature and stratified the reported prognostic factors into categories that reflected the strength of the published evidence demonstrating their prognostic value. Accordingly, the following categories of prognostic factors were defined. Category I includes factors definitively proven to be of prognostic import based on evidence from multiple statistically robust published trials and generally used in patient management. Category IIA includes factors extensively studied biologically and/or clinically and repeatedly shown to have prognostic value for outcome and/or predictive value for therapy that is of sufficient import to be included in the pathology report but that remains to be validated in statistically robust studies. Category IIB includes factors shown to be promising in multiple studies but lacking sufficient data for inclusion in category I or IIA. Category III includes factors not yet sufficiently studied to determine their prognostic value. Category IV includes factors well studied and shown to have no prognostic significance. Materials and methods The medical literature was critically reviewed, and the analysis revealed specific points of variability in approach that prevented direct comparisons among published studies and compromised the quality of the collective data. Categories of variability recognized included the following: (1) methods of analysis, (2) interpretation of findings, (3) reporting of data, and (4) statistical evaluation. Additional points of variability within these categories were defined from the collective experience of the group. Reasons for the assignment of an individual prognostic factor to category I, II, III, or IV (categories defined by the level of scientific validation) were outlined with reference to the specific types of variability associated with the supportive data. For each factor and category of variability related to that factor, detailed recommendations for improvement were made. The recommendations were based on the following aims: (1) to increase the uniformity and completeness of pathologic evaluation of tumor specimens, (2) to enhance the quality of the data needed for definitive evaluation of the prognostic value of individual prognostic factors, and (3) ultimately, to improve patient care. Results and conclusions Factors that were determined to merit inclusion in category I were as follows: the local extent of tumor assessed pathologically (the pT category of the TNM staging system of the American Joint Committee on Cancer and the Union Internationale Contre le Cancer [AJCC/UICC]); regional lymph node metastasis (the pN category of the TNM staging system); blood or lymphatic vessel invasion; residual tumor following surgery with curative intent (the R classification of the AJCC/UICC staging system), especially as it relates to positive surgical margins; and preoperative elevation of carcinoembryonic antigen elevation (a factor established by laboratory medicine methods rather than anatomic pathology). Factors in category IIA included the following: tumor grade, radial margin status (for resection specimens with nonperitonealized surfaces), and residual tumor in the resection specimen following neoadjuvant therapy (the ypTNM category of the TNM staging system of the AJCC/UICC). (ABSTRACT TRUNCATED)

Rethinking Environmental Racism: White Privilege and Urban Development in Southern California

Abstract: Geographic studies of environmental racism have focused on the spatial relationships between environmental hazards and community demographics in order to determine if inequity exists. Conspicuously absent within this literature, however, is any substantive discussion of racism. This paper seeks to address this shortcoming in two ways. I first investigate how racism is understood and expressed in the literature. I argue that although racism is rarely explicitly discussed, a normative conceptualization of racism informs the research. Not only is this prevailing conception overly narrow and restrictive, it also denies the spatiality of racism. Consequently, my second goal is to demonstrate how various forms of racism contribute to environmental racism. In addition to conventional understandings of racism, I emphasize white privilege, a highly structural and spatial form of racism. Using Los Angeles as a case study, I examine how whites have secured relatively cleaner environments by moving away from older in...

Etanercept in Children with Polyarticular Juvenile Rheumatoid Arthritis

Abstract: Background We evaluated the safety and efficacy of etanercept, a soluble tumor necrosis factor receptor (p75):Fc fusion protein, in children with polyarticular juvenile rheumatoid arthritis who did not tolerate or had an inadequate response to methotrexate. Methods Patients 4 to 17 years old received 0.4 mg of etanercept per kilogram of body weight subcutaneously twice weekly for up to three months in the initial, open-label part of a multicenter trial. Those who responded to treatment then entered a double-blind study and were randomly assigned to receive either placebo or etanercept for four months or until a flare of the disease occurred. A response was defined as an improvement of 30 percent or more in at least three of six indicators of disease activity, with no more than one indicator worsening by more than 30 percent. Results At the end of the open-label study, 51 of the 69 patients (74 percent) had had responses to etanercept treatment. In the double-blind study, 21 of the 26 patients who received...

Urinary and sexual function after radical prostatectomy for clinically localized prostate cancer : The Prostate Cancer Outcomes Study

Abstract: ContextPatients with prostate cancer and their physicians need knowledge of treatment options and their potential complications, but limited data on complications are available in unselected population-based cohorts of patients.ObjectiveTo measure changes in urinary and sexual function in men who have undergone radical prostatectomy for clinically localized prostate cancer.DesignThe Prostate Cancer Outcomes Study, a population-based longitudinal cohort study with up to 24 months of follow-up.SettingPopulation-based cancer registries in 6 geographic regions of the United States.ParticipantsA total of 1291 black, white, and Hispanic men aged 39 to 79 years who were diagnosed as having primary prostate cancer between October 1, 1994, and October 31, 1995, and who underwent radical prostatectomy within 6 months of diagnosis for clinically localized disease.Main Outcome MeasuresDistribution of and change in urinary and sexual function measures reported by patients at baseline and 6, 12, and 24 months after diagnosis.ResultsAt 18 or more months following radical prostatectomy, 8.4% of men were incontinent and 59.9% were impotent. Among men who were potent before surgery, the proportion of men reporting impotence at 18 or more months after surgery varied according to whether the procedure was nerve sparing (65.6% of non–nerve-sparing, 58.6% of unilateral, and 56.0% of bilateral nerve–sparing). At 18 or more months after surgery, 41.9% reported that their sexual performance was a moderate-to-large problem. Both sexual and urinary function varied by age (39.0% of men aged <60 years vs 15.3%-21.7% of older men were potent at ≥18 months [P<.001]; 13.8% of men aged 75-79 years vs 0.7%-3.6% of younger men experienced the highest level of incontinence at ≥18 months [P = .03]), and sexual function also varied by race (38.4% of black men reported firm erections at ≥18 months vs 25.9% of Hispanic and 21.3% of white men; P = .001).ConclusionsOur study suggests that radical prostatectomy is associated with significant erectile dysfunction and some decline in urinary function. These results may be particularly helpful to community-based physicians and their patients with prostate cancer who face difficult treatment decisions.

Mice Deficient in Cellular Glutathione Peroxidase Show Increased Vulnerability to Malonate, 3-Nitropropionic Acid, and 1-Methyl-4-Phenyl-1,2,5,6-Tetrahydropyridine

Abstract: Glutathione peroxidase (GSHPx) is a critical intracellular enzyme involved in detoxification of hydrogen peroxide (H 2 O 2 ) to water. In the present study we examined the susceptibility of mice with a disruption of the glutathione peroxidase gene to the neurotoxic effects of malonate, 3-nitropropionic acid (3-NP), and 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP). Glutathione peroxidase knock-out mice showed no evidence of neuropathological or behavioral abnormalities at 2–3 months of age. Intrastriatal injections of malonate resulted in a significant twofold increase in lesion volume in homozygote GSHPx knock-out mice as compared to both heterozygote GSHPx knock-out and wild-type control mice. Malonate-induced increases in conversion of salicylate to 2,3- and 2,5-dihydroxybenzoic acid, an index of hydroxyl radical generation, were greater in homozygote GSHPx knock-out mice as compared with both heterozygote GSHPx knock-out and wild-type control mice. Administration of MPTP resulted in significantly greater depletions of dopamine, 3,4-dihydroxybenzoic acid, and homovanillic acid in GSHPx knock-out mice than those seen in wild-type control mice. Striatal 3-nitrotyrosine (3-NT) concentrations after MPTP were significantly increased in GSHPx knock-out mice as compared with wild-type control mice. Systemic 3-NP administration resulted in significantly greater striatal damage and increases in 3-NT in GSHPx knock-out mice as compared to wild-type control mice. The present results indicate that a knock-out of GSHPx may be adequately compensated under nonstressed conditions, but that after administration of mitochondrial toxins GSHPx plays an important role in detoxifying increases in oxygen radicals.

Fate of the mammalian cardiac neural crest.

Abstract: A subpopulation of neural crest termed the cardiac neural crest is required in avian embryos to initiate reorganization of the outflow tract of the developing cardiovascular system. In mammalian embryos, it has not been previously experimentally possible to study the long-term fate of this population, although there is strong inference that a similar population exists and is perturbed in a number of genetic and teratogenic contexts. We have employed a two-component genetic system based on Cre/lox recombination to label indelibly the entire mouse neural crest population at the time of its formation, and to detect it at any time thereafter. Labeled cells are detected throughout gestation and in postnatal stages in major tissues that are known or predicted to be derived from neural crest. Labeling is highly specific and highly efficient. In the region of the heart, neural-crest-derived cells surround the pharyngeal arch arteries from the time of their formation and undergo an altered distribution coincident with the reorganization of these vessels. Labeled cells populate the aorticopulmonary septum and conotruncal cushions prior to and during overt septation of the outflow tract, and surround the thymus and thyroid as these organs form. Neural-crest-derived mesenchymal cells are abundantly distributed in midgestation (E9.5-12.5), and adult derivatives of the third, fourth and sixth pharyngeal arch arteries retain a substantial contribution of labeled cells. However, the population of neural-crest-derived cells that infiltrates the conotruncus and which surrounds the noncardiac pharyngeal organs is either overgrown or selectively eliminated as development proceeds, resulting for these tissues in a modest to marginal contribution in late fetal and postnatal life.

High-efficiency organic electrophosphorescent devices with tris(2-phenylpyridine)iridium doped into electron-transporting materials

Abstract: We demonstrate high-efficiency organic light-emitting devices employing the green electrophosphorescent molecule, fac tris(2-phenylpyridine)iridium [Ir(ppy)3], doped into various electron-transport layer (ETL) hosts. Using 3-phenyl-4-(1′-naphthyl)-5-phenyl-1,2,4-triazole as the host, a maximum external quantum efficiency (ηext) of 15.4±0.2% and a luminous power efficiency of 40±2 Im/W are achieved. We show that very high internal quantum efficiencies (approaching 100%) are achieved for organic phosphors with low photoluminescence efficiencies due to fundamental differences in the relationship between electroluminescence from triplet and singlet excitons. Based on the performance characteristics of single and double heterostructures, we conclude that exciton formation in Ir(ppy)3 occurs within close proximity to the hole-transport layer/ETL:Ir(ppy)3 interface.

Exposure measurement error in time-series studies of air pollution: concepts and consequences.

Abstract: Misclassification of exposure is a well-recognized inherent limitation of epidemiologic studies of disease and the environment. For many agents of interest, exposures take place over time and in multiple locations; accurately estimating the relevant exposures for an individual participant in epidemiologic studies is often daunting, particularly within the limits set by feasibility, participant burden, and cost. Researchers have taken steps to deal with the consequences of measurement error by limiting the degree of error through a study's design, estimating the degree of error using a nested validation study, and by adjusting for measurement error in statistical analyses. In this paper, we address measurement error in observational studies of air pollution and health. Because measurement error may have substantial implications for interpreting epidemiologic studies on air pollution, particularly the time-series analyses, we developed a systematic conceptual formulation of the problem of measurement error in epidemiologic studies of air pollution and then considered the consequences within this formulation. When possible, we used available relevant data to make simple estimates of measurement error effects. This paper provides an overview of measurement errors in linear regression, distinguishing two extremes of a continuum-Berkson from classical type errors, and the univariate from the multivariate predictor case. We then propose one conceptual framework for the evaluation of measurement errors in the log-linear regression used for time-series studies of particulate air pollution and mortality and identify three main components of error. We present new simple analyses of data on exposures of particulate matter < 10 microm in aerodynamic diameter from the Particle Total Exposure Assessment Methodology Study. Finally, we summarize open questions regarding measurement error and suggest the kind of additional data necessary to address them.

The Incumbent's Curse? Incumbency, Size, and Radical Product Innovation

Abstract: A common perception in the field of innovation is that large, incumbent firms rarely introduce radical product innovations. Such firms tend to solidify their market positions with relatively incremental innovations. They may even turn away entrepreneurs who come up with radical innovations, though they themselves had such entrepreneurial roots. As a result, radical innovations tend to come from small firms, the outsiders. This thesis, which we term the “incumbent’s curse,” is commonly accepted in academic and popular accounts of radical innovation. This topic is important, because radical product innovation is an engine of economic growth that has created entire industries and brought down giants while catapulting small firms to market leadership. Yet a review of the literature suggests that the evidence for the incumbent’s curse is based on anecdotes and scattered case studies of highly specialized innovations. It is not clear if it applies widely across several product categories. The authors r...

Practice Guidelines for the Management of Cryptococcal Disease

Abstract: An 8-person subcommittee of the National Institute of Allergy and Infectious Diseases (NIAID) Mycoses Study Group evaluated available data on the treatment of cryptococcal disease. Opinion regarding optimal treatment was based on personal experience and information in the literature. The relative strength of each recommendation was graded according to the type and degree of evidence available to support the recommendation, in keeping with previously published guidelines by the Infectious Diseases Society of America (IDSA). The panel conferred in person (on 2 occasions), by conference call, and through written reviews of each draft of the manuscript. The choice of treatment for disease caused by Cryptococcus neoformans depends on both the anatomic sites of involvement and the host's immune status. For immunocompetent hosts with isolated pulmonary disease, careful observation may be warranted; in the case of symptomatic infection, indicated treatment is fluconazole, 200-400 mg/day for 36 months. For those individuals with non-CNS-isolated cryptococcemia, a positive serum cryptococcal antigen titer >1:8, or urinary tract or cutaneous disease, recommended treatment is oral azole therapy (fluconazole) for 36 months. In each case, careful assessment of the CNS is required to rule out occult meningitis. For those individuals who are unable to tolerate fluconazole, itraconazole (200-400 mg/day for 6-12 months) is an acceptable alternative. For patients with more severe disease, treatment with amphotericin B (0.5-1 mg/kg/d) may be necessary for 6-10 weeks. For otherwise healthy hosts with CNS disease, standard therapy consists of amphotericin B, 0.7-1 mg/kg/d, plus flucytosine, 100 mg/kg/d, for 6-10 weeks. An alternative to this regimen is amphotericin B (0.7-1 mg/kg/d) plus 5-flucytosine (100 mg/kg/d) for 2 weeks, followed by fluconazole (400 mg/day) for a minimum of 10 weeks. Fluconazole "consolidation" therapy may be continued for as along as 6-12 months, depending on the clinical status of the patient. HIV-negative, immunocompromised hosts should be treated in the same fashion as those with CNS disease, regardless of the site of involvement. Cryptococcal disease that develops in patients with HIV infection always warrants therapy. For those patients with HIV who present with isolated pulmonary or urinary tract disease, fluconazole at 200-400 mg/d is indicated. Although the ultimate impact from highly active antiretroviral therapy (HAART) is currently unclear, it is recommended that all HIV-infected individuals continue maintenance therapy for life. Among those individuals who are unable to tolerate fluconazole, itraconazole (200-400 mg/d) is an acceptable alternative. For patients with more severe disease, a combination of fluconazole (400 mg/d) plus flucytosine (100-150 mg/d) may be used for 10 weeks, followed by fluconazole maintenance therapy. Among patients with HIV infection and cryptococcal meningitis, induction therapy with amphotericin B (0.7-1 mg/kg/d) plus flucytosine (100 mg/kg/d for 2 weeks) followed by fluconazole (400 mg/d) for a minimum of 10 weeks is the treatment of choice. After 10 weeks of therapy, the fluconazole dosage may be reduced to 200 mg/d, depending on the patient's clinical status. Fluconazole should be continued for life. An alternative regimen for AIDS-associated cryptococcal meningitis is amphotericin B (0.7-1 mg/kg/d) plus 5-flucytosine (100 mg/kg/d) for 6-10 weeks, followed by fluconazole maintenance therapy. Induction therapy beginning with an azole alone is generally discouraged. Lipid formulations of amphotericin B can be substituted for amphotericin B for patients whose renal function is impaired. Fluconazole (400-800 mg/d) plus flucytosine (100-150 mg/kg/d) for 6 weeks is an alternative to the use of amphotericin B, although toxicity with this regimen is high. In all cases of cryptococcal meningitis, careful attention to the management of intracranial pressure is imperative to assure optimal c

The importance of repairing stalled replication forks

Abstract: The bacterial SOS response to unusual levels of DNA damage has been recognized and studied for several decades. Pathways for re-establishing inactivated replication forks under normal growth conditions have received far less attention. In bacteria growing aerobically in the absence of SOS-inducing conditions, many replication forks encounter DNA damage, leading to inactivation. The pathways for fork reactivation involve the homologous recombination systems, are nonmutagenic, and integrate almost every aspect of DNA metabolism. On a frequency-of-use basis, these pathways represent the main function of bacterial DNA recombination systems, as well as the main function of a number of other enzymatic systems that are associated with replication and site-specific recombination.

Reduced prefrontal gray matter volume and reduced autonomic activity in antisocial personality disorder.

Abstract: Background: Major damage to gray and white matter in the prefrontal cortex and autonomic deficits have been found to result in pseudopsychopathic personality in patients with neurological disorders, but it is not known whether people with antisocial personality disorder (APD) in the community who do not have discernable brain trauma also have subtle prefrontal deficits. Methods: Prefrontal gray and white matter volumes were assessed using structural magnetic resonance imaging in 21 community volunteers with APD (APD group) and in 2 control groups, comprising 34 healthy subjects (control group), 26 subjects with substance dependence (substancedependent group), and 21 psychiatric controls. Autonomic activity (skin conductance and heart rate) was also assessed during a social stressor in which participants gave a videotaped speech on their faults. Results: TheAPD group showed an 11.0% reduction in prefrontal gray matter volume in the absence of ostensible brain lesions and reduced autonomic activity during the stressor. These deficits predicted group membership independent of psychosocial risk factors. Conclusions: To our knowledge, these findings provide the first evidence for a structural brain deficit in APD. This prefrontal structural deficit may underlie the low arousal, poor fear conditioning, lack of conscience, and decision-making deficits that have been found to characterize antisocial, psychopathic behavior. Arch Gen Psychiatry. 2000;57:119-127

Low (Sub-1-Volt) Halfwave Voltage Polymeric Electro-optic Modulators Achieved by Controlling Chromophore Shape

Abstract: Electro-optic (EO) modulators encode electrical signals onto fiber optic transmissions. High drive voltages limit gain and noise levels. Typical polymeric and lithium niobate modulators operate with halfwave voltages of 5 volts. Sterically modified organic chromophores have been used to reduce the attenuation of electric field poling-induced electro-optic activity caused by strong intermolecular electrostatic interactions. Such modified chromophores, incorporated into polymer hosts, were used to fabricate EO modulators with halfwave voltages of 0.8 volts (at a telecommunications wavelength of 1318 nanometers) and to achieve a halfwave voltage-interaction length product of 2.2 volt-centimeters. Optical push-pull poling and driving were also used to reduce halfwave voltage. This study, together with recent demonstrations of exceptional bandwidths (more than 110 gigahertz) and ease of integration (with very large scale integration semiconductor circuitry and ultra-low-loss passive optical circuitry) demonstrates the potential of polymeric materials for next generation telecommunications, information processing, and radio frequency distribution.

Colorectal Tumors Responding to 5-Fluorouracil Have Low Gene Expression Levels of Dihydropyrimidine Dehydrogenase, Thymidylate Synthase, and Thymidine Phosphorylase

Abstract: We had previously shown that high gene expressions (mRNA levels) of thymidylate synthase (TS; Leichman et al., J. Clin. Oncol., 15: 3223-3229, 1997) and thymidine phosphorylase (TP; Metzger et al., Clin. Cancer Res., 4: 2371-2376, 1998) in pretreatment tumor biopsies could identify tumors that would be nonresponsive to 5-fluorouracil (5-FU)-based therapy. In this study, we investigated the association between intratumoral gene expression of the pyrimidine catabolism enzyme dihydropyrimidine dehydrogenase (DPD) and the response of colorectal tumors to the same 5-FU-based protocol. DPD expressions were measured by quantitative reverse transcription-PCR in 33 pretreatment biopsies of colorectal tumors from patients who went on to receive treatment with 5-FU and leucovorin (LV). The range of DPD gene expression in those tumors that were nonresponsive to 5-FU was much broader than that of the responding tumors. None of the tumors with basal-level DPD expressions above a DPD:beta-actin ratio of 2.5 x 10(-3) (14 of 33) were responders to 5-FU/LV therapy, whereas those tumors with DPD gene expressions below DPD: beta-actin ratio of 2.5 x 10(-3) had a response rate of 50%. There was no correlation among DPD, TS, and TP expression values in this set of colorectal tumors, which indicated that these gene expressions are independent variables. All of the tumors that responded to 5-FU therapy (11 of 33) had expression values of all three of the genes, TS, TP, and DPD, below their respective nonresponse cutoff values, whereas, in each of the nonresponding tumors, at least one of these gene expressions was high. The patients with low expression of all three of the genes had significantly longer survival than patients with a high value of any one of the gene expressions. The results of this study show that intratumoral gene expression level of DPD is associated with tumor response to 5-FU and that the use of more than one independent determinant of response permits the identification of a high percentage of responding patients.

Oxidative stress, antioxidant defenses, and damage removal, repair, and replacement systems.

Abstract: Oxidative stress is an unavoidable consequence of life in an oxygen-rich atmosphere. Oxygen radicals and other activated oxygen species are generated as by-products of aerobic metabolism and exposure to various natural and synthetic toxicants. The "Oxygen Paradox" is that oxygen is dangerous to the very life-forms for which it has become an essential component of energy production. The first defense against oxygen toxicity is the sharp gradient of oxygen tension, seen in all mammals, from the environmental level of 20% to a tissue concentration of only 3-4% oxygen. These relatively low tissue levels of oxygen prevent most oxidative damage from ever occurring. Cells, tissues, organs, and organisms utilize multiple layers of antioxidant defenses and damage removal, and replacement or repair systems in order to cope with the remaining stress and damage that oxygen engenders. The enzymes comprising many of these protective systems are inducible under conditions of oxidative stress adaptation, in which the expression of over 40 mammalian genes is upregulated. Mitotic cells have the additional defensive ability of entering a transient growth-arrested state (in the first stages of adaptation) in which DNA is protected by histone proteins, energy is conserved by diminished expression of nonessential genes, and the expression of shock and stress proteins is greatly increased. Failure to fully cope with an oxidative stress can switch mitotic cells into a permanent growth-arrested, senescence-like state in which they may survive for long periods. Faced with even more severe oxidative stress, or the declining protective enzymes and adaptive capacity associated with aging, cells may "sacrifice themselves" by apoptosis, which protects surrounding healthy tissue from further damage. Only under the most severe oxidative stress conditions will cells undergo a necrotic death, which exposes surrounding tissues to the further vicissitudes of an inflammatory immune response. This remarkable array of systems for defense; damage removal, replacement, and repair; adaptation; growth modulation; and apoptosis make it possible for us to enjoy life in an oxygen-rich environment.