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Showing papers by "University of Maryland, Baltimore published in 2002"


Journal ArticleDOI
TL;DR: State-of-the-art information is presented and insights are provided into the strengths and limitations of high-resolution ultrasonography of the brachial artery to evaluate vasomotor function, with guidelines for its research application in the study of endothelial physiology.

4,604 citations


Journal ArticleDOI
TL;DR: Topical ocular hypotensive medication was effective in delaying or preventing the onset of POAG in individuals with elevated IOP, and clinicians should consider initiating treatment for individuals with ocular hypertension who are at moderate or high risk for developing POAG.
Abstract: Background Primary open-angle glaucoma (POAG) is one of the leading causes of blindness in the United States and worldwide. Three to 6 million people in the United States are at increased risk for developing POAG because of elevated intraocular pressure (IOP), or ocular hypertension. There is no consensus on the efficacy of medical treatment in delaying or preventing the onset of POAG in individuals with elevated IOP. Therefore, we designed a randomized clinical trial, the Ocular Hypertension Treatment Study. Objective To determine the safety and efficacy of topical ocular hypotensive medication in delaying or preventing the onset of POAG. Methods A total of 1636 participants with no evidence of glaucomatous damage, aged 40 to 80 years, and with an IOP between 24 mm Hg and 32 mm Hg in one eye and between 21 mm Hg and 32 mm Hg in the other eye were randomized to either observation or treatment with commercially available topical ocular hypotensive medication. The goal in the medication group was to reduce the IOP by 20% or more and to reach an IOP of 24 mm Hg or less. Main Outcome Measures The primary outcome was the development of reproducible visual field abnormality or reproducible optic disc deterioration attributed to POAG. Abnormalities were determined by masked certified readers at the reading centers, and attribution to POAG was decided by the masked Endpoint Committee. Results During the course of the study, the mean ± SD reduction in IOP in the medication group was 22.5% ± 9.9%. The IOP declined by 4.0%± 11.6% in the observation group. At 60 months, the cumulative probability of developing POAG was 4.4% in the medication group and 9.5% in the observation group (hazard ratio, 0.40; 95% confidence interval, 0.27-0.59; P Conclusions Topical ocular hypotensive medication was effective in delaying or preventing the onset of POAG in individuals with elevated IOP. Although this does not imply that all patients with borderline or elevated IOP should receive medication, clinicians should consider initiating treatment for individuals with ocular hypertension who are at moderate or high risk for developing POAG.

3,487 citations


Journal ArticleDOI
TL;DR: Baseline age, vertical and horizontal cup-disc ratio, pattern standard deviation, and intraocular pressure were good predictors for the onset of POAG in the OHTS and central corneal thickness was found to be a powerful predictor for the development ofPOAG.
Abstract: Background The Ocular Hypertension Treatment Study (OHTS) has shown that topical ocular hypotensive medication is effective in delaying or preventing the onset of primary open-angle glaucoma (POAG) in individuals with elevated intraocular pressure (ocular hypertension) and no evidence of glaucomatous damage. Objective To describe baseline demographic and clinical factors that predict which participants in the OHTS developed POAG. Methods Baseline demographic and clinical data were collected prior to randomization except for corneal thickness measurements, which were performed during follow-up. Proportional hazards models were used to identify factors that predicted which participants in the OHTS developed POAG. Results In univariate analyses, baseline factors that predicted the development of POAG included older age, race (African American), sex (male), larger vertical cup-disc ratio, larger horizontal cup-disc ratio, higher intraocular pressure, greater Humphrey visual field pattern standard deviation, heart disease, and thinner central corneal measurement. In multivariate analyses, baseline factors that predicted the development of POAG included older age, larger vertical or horizontal cup-disc ratio, higher intraocular pressure, greater pattern standard deviation, and thinner central corneal measurement. Conclusions Baseline age, vertical and horizontal cup-disc ratio, pattern standard deviation, and intraocular pressure were good predictors for the onset of POAG in the OHTS. Central corneal thickness was found to be a powerful predictor for the development of POAG.

2,279 citations


Journal ArticleDOI
TL;DR: The complete genome sequence of uropathogenic Escherichia coli, strain CFT073 is presented and Comparisons indicate that extraintestinal pathogenic E. coli arose independently from multiple clonal lineages.
Abstract: We present the complete genome sequence of uropathogenic Escherichia coli, strain CFT073. A three-way genome comparison of the CFT073, enterohemorrhagic E. coli EDL933, and laboratory strain MG1655 reveals that, amazingly, only 39.2% of their combined (nonredundant) set of proteins actually are common to all three strains. The pathogen genomes are as different from each other as each pathogen is from the benign strain. The difference in disease potential between O157:H7 and CFT073 is reflected in the absence of genes for type III secretion system or phage- and plasmid-encoded toxins found in some classes of diarrheagenic E. coli. The CFT073 genome is particularly rich in genes that encode potential fimbrial adhesins, autotransporters, iron-sequestration systems, and phase-switch recombinases. Striking differences exist between the large pathogenicity islands of CFT073 and two other well-studied uropathogenic E. coli strains, J96 and 536. Comparisons indicate that extraintestinal pathogenic E. coli arose independently from multiple clonal lineages. The different E. coli pathotypes have maintained a remarkable synteny of common, vertically evolved genes, whereas many islands interrupting this common backbone have been acquired by different horizontal transfer events in each strain.

1,483 citations


Journal ArticleDOI
16 Oct 2002-JAMA
TL;DR: Applying these approaches to the general population as a component of public health and clinical practice can help prevent blood pressure from increasing and can help decrease elevated blood pressure levels for those with high normal blood pressure or hypertension.
Abstract: The National High Blood Pressure Education Program Coordinating Committee published its first statement on the primary prevention of hypertension in 1993. This article updates the 1993 report, using new and further evidence from the scientific literature. Current recommendations for primary prevention of hypertension involve a population-based approach and an intensive targeted strategy focused on individuals at high risk for hypertension. These 2 strategies are complementary and emphasize 6 approaches with proven efficacy for prevention of hypertension: engage in moderate physical activity; maintain normal body weight; limit alcohol consumption; reduce sodium intake; maintain adequate intake of potassium; and consume a diet rich in fruits, vegetables, and low-fat dairy products and reduced in saturated and total fat. Applying these approaches to the general population as a component of public health and clinical practice can help prevent blood pressure from increasing and can help decrease elevated blood pressure levels for those with high normal blood pressure or hypertension.

1,478 citations


Journal ArticleDOI
03 May 2002-Science
TL;DR: Higher order chromatin structure presents a barrier to the recognition and repair of DNA damage, and H2AX is critical for facilitating the assembly of specific DNA-repair complexes on damaged DNA.
Abstract: Higher order chromatin structure presents a barrier to the recognition and repair of DNA damage. Double-strand breaks (DSBs) induce histone H2AX phosphorylation, which is associated with the recruitment of repair factors to damaged DNA. To help clarify the physiological role of H2AX, we targeted H2AX in mice. Although H2AX is not essential for irradiation-induced cell-cycle checkpoints, H2AX −/− mice were radiation sensitive, growth retarded, and immune deficient, and mutant males were infertile. These pleiotropic phenotypes were associated with chromosomal instability, repair defects, and impaired recruitment of Nbs1, 53bp1, and Brca1, but not Rad51, to irradiation-induced foci. Thus, H2AX is critical for facilitating the assembly of specific DNA-repair complexes on damaged DNA.

1,387 citations


Journal ArticleDOI
03 Oct 2002-Nature
TL;DR: A high-throughput proteomics approach was applied to identify new potential drug and vaccine targets and to better understand the biology of this complex protozoan parasite.
Abstract: The completion of the Plasmodium falciparum clone 3D7 genome provides a basis on which to conduct comparative proteomics studies of this human pathogen. Here, we applied a high-throughput proteomics approach to identify new potential drug and vaccine targets and to better understand the biology of this complex protozoan parasite. We characterized four stages of the parasite life cycle (sporozoites, merozoites, trophozoites and gametocytes) by multidimensional protein identification technology. Functional profiling of over 2,400 proteins agreed with the physiology of each stage. Unexpectedly, the antigenically variant proteins of var and rif genes, defined as molecules on the surface of infected erythrocytes, were also largely expressed in sporozoites. The detection of chromosomal clusters encoding co-expressed proteins suggested a potential mechanism for controlling gene expression.

1,314 citations


Journal ArticleDOI
TL;DR: In this paper, it was shown that the major ROS-generating site in mitochondria is limited to the flavin mononucleotide group (FMN) of complex I through reversed electron transfer, not at the ubiquinone of complex III.
Abstract: Generation of reactive oxygen species (ROS) by the mitochondrial electron transport chain (ETC), which is composed of four multiprotein complexes named complex I-IV, is believed to be important in the aging process and in the pathogenesis of neurodegenerative diseases such as Parkinson's disease. Previous studies have identified the ubiquinone of complex III and an unknown component of complex I as the major sites of ROS generation. Here we show that the physiologically relevant ROS generation supported by the complex II substrate succinate occurs at the flavin mononucleotide group (FMN) of complex I through reversed electron transfer, not at the ubiquinone of complex III as commonly believed. Indirect evidence indicates that the unknown ROS-generating site within complex I is also likely to be the FMN group. It is therefore suggested that the major physiologically and pathologically relevant ROS-generating site in mitochondria is limited to the FMN group of complex I. These new insights clarify an elusive target for intervening mitochondrial ROS-related processes or diseases.

1,180 citations


Journal ArticleDOI
TL;DR: Increasing AHI was associated with worsening insulin resistance independent of obesity and Multivariable linear regression analyses revealed that sleep-disordered breathing is a prevalent condition in mildly obese men and is independently associated with glucose intolerance and insulin resistance.
Abstract: Sleep-disordered breathing is a prevalent condition associated with impairment of daytime function and may predispose individuals to metabolic abnormalities independent of obesity. The primary objective of this study was to determine the metabolic consequences and community prevalence of sleep-disordered breathing in mildly obese, but otherwise healthy, individuals. One hundred and fifty healthy men, without diabetes or cardiopulmonary disease, were recruited from the community. Measurements included polysomnography, a multiple sleep latency test, an oral glucose tolerance test, determination of body fat by hydrodensitometry, and fasting insulin and lipids. The prevalence of sleep-disordered breathing, depending on the apnea-hypopnea index (AHI) cutoff, ranged from 40 to 60%. After adjusting for body mass index (BMI) and percent body fat, an AHI gt-or-equal, slanted 5 events/h was associated with an increased risk of having impaired or diabetic glucose tolerance (odds ratio, 2.15; 95% CI, 1.05-4.38). The impairment in glucose tolerance was related to the severity of oxygen desaturation (DeltaSa(O(2))) associated with sleep-disordered breathing. For a 4% decrease in oxygen saturation, the associated odds ratio for worsening glucose tolerance was 1.99 (95% CI, 1.11 to 3.56) after adjusting for percent body fat, BMI, and AHI. Multivariable linear regression analyses revealed that increasing AHI was associated with worsening insulin resistance independent of obesity. Thus, sleep-disordered breathing is a prevalent condition in mildly obese men and is independently associated with glucose intolerance and insulin resistance.

926 citations


Journal ArticleDOI
TL;DR: The authors found that in the 1970s and 1980s much attention was given to the need for and the development of professional competencies for many medical disciplines, little attention was devoted to defining the benchmarks of specific competencies, how to attain them, or the evaluation of competence.
Abstract: Realizing medical education is on the brink of a major paradigm shift from structure- and process-based to competency-based education and measurement of outcomes, the authors reviewed the existing medical literature to provide practical insight into how to accomplish full implementation and evaluation of this new paradigm. They searched Medline and the Educational Resource Information Clearinghouse from the 1960s until the present, reviewed the titles and abstracts of the 469 articles the search produced, and chose 68 relevant articles for full review. The authors found that in the 1970s and 1980s much attention was given to the need for and the development of professional competencies for many medical disciplines. Little attention, however, was devoted to defining the benchmarks of specific competencies, how to attain them, or the evaluation of competence. Lack of evaluation strategies was likely one of the forces responsible for the threedecade lag between initiation of the movement and widespread adoption. Lessons learned from past experiences include the importance of strategic planning and faculty and learner buy-in for defining competencies. In addition, the benchmarks for defining competency and the thresholds for attaining competence must be clearly delineated. The development of appropriate assessment tools to measure competence remains the challenge of this decade, and educators must be responsible for studying the impact of this paradigm shift to determine whether its ultimate effect is the production of more competent physicians. Acad. Med. 2002;77:361‐367.

866 citations


Journal ArticleDOI
TL;DR: In this article, the authors show that an increase in Forster transfer distances and directional transfer distances has hindered fluorescence growth from further minor effects on the fluorophores free-space spectral revolutionalizing the analytical and clinical sciences.
Abstract: As fluorescence spectroscopists we are mostly all yields, decreased lifetimes, increased photostability, and familiar with doing spectroscopy in bulk samples, where an increase in Forster transfer distances and directional the solutions are typically transparent to the emitted radia- emission Such opportunities are truly refreshing, because tion, and the fluorophores emit isotropically into free although fluorescence methodology and subsequent space and are observed in the far field There may be applications are routinely practiced in many laboratories changes in the refractive index, such as for a fluorophore around the world, little research on such basic principles in a membrane, but these changes typically have only has probably hindered fluorescence growth from further minor effects on the fluorophores free-space spectral revolutionalizing the analytical and clinical sciences For properties

Journal ArticleDOI
TL;DR: Patients with limbs at high risk for amputation can be advised that reconstruction typically results in two-year outcomes equivalent to those of amputation.
Abstract: Background Limb salvage for severe trauma has replaced amputation as the primary treatment in many trauma centers. However, long-term outcomes after limb reconstruction or amputation have not been fully evaluated. Methods We performed a multicenter, prospective, observational study to determine the functional outcomes of 569 patients with severe leg injuries resulting in reconstruction or amputation. The principal outcome measure was the Sickness Impact Profile, a multidimensional measure of self-reported health status (scores range from 0 to 100; scores for the general population average 2 to 3, and scores greater than 10 represent severe disability). Secondary outcomes included limb status and the presence or absence of major complications resulting in rehospitalization. Results At two years, there was no significant difference in scores for the Sickness Impact Profile between the amputation and reconstruction groups (12.6 vs. 11.8, P=0.53). After adjustment for the characteristics of the patients and t...

Journal ArticleDOI
TL;DR: If the observed associations are causal, then intervention programmes designed to prevent malnutrition and G lamblia early in life could lead to significant improvement in cognitive function of children in similar lower-income communities throughout the less-developed world.

Journal ArticleDOI
TL;DR: These results expand published findings demonstrating that immunization by exposure to thousands of mosquitoes carrying radiation-attenuated Pf sporozoites is safe and well tolerated and elicits strain-transcendent protective immunity that persists for at least 42 weeks.
Abstract: During 1989-1999, 11 volunteers were immunized by the bites of 1001-2927 irradiated mosquitoes harboring infectious sporozoites of Plasmodium falciparum (Pf) strain NF54 or clone 3D7/NF54. Ten volunteers were first challenged by the bites of Pf-infected mosquitoes 2-9 weeks after the last immunization, and all were protected. A volunteer challenged 10 weeks after the last immunization was not protected. Five previously protected volunteers were rechallenged 23-42 weeks after a secondary immunization, and 4 were protected. Two volunteers were protected when rechallenged with a heterologous Pf strain (7G8). In total, there was protection in 24 of 26 challenges. These results expand published findings demonstrating that immunization by exposure to thousands of mosquitoes carrying radiation-attenuated Pf sporozoites is safe and well tolerated and elicits strain-transcendent protective immunity that persists for at least 42 weeks.

Journal ArticleDOI
TL;DR: It is shown that leukemic cells from every individual with DS-AMKL contain mutations in GATA1, encoding the essential hematopoietic transcription factor Gata1 (GATA binding protein 1 or globin transcription factor 1), and that loss of wildtype GATA 1 constitutes one step in the pathogenesis of AMKL in Down syndrome.
Abstract: Children with Down syndrome have a 10–20-fold elevated risk of developing leukemia, particularly acute megakaryoblastic leukemia (AMKL)1. While a subset of pediatric AMKLs is associated with the 1;22 translocation and expression of a mutant fusion protein2,3, the genetic alterations that promote Down syndrome–related AMKL (DS-AMKL) have remained elusive. Here we show that leukemic cells from every individual with DS-AMKL that we examined contain mutations in GATA1, encoding the essential hematopoietic transcription factor GATA1 (GATA binding protein 1 or globin transcription factor 1). Each mutation results in the introduction of a premature stop codon in the gene sequence that encodes the amino-terminal activation domain. These mutations prevent synthesis of full-length GATA1, but not synthesis of a shorter variant that is initiated downstream. We show that the shorter GATA1 protein, which lacks the N-terminal activation domain, binds DNA and interacts with its essential cofactor Friend of GATA1 (FOG1; encoded by ZFPM1)4 to the same extent as does full-length GATA1, but has a reduced transactivation potential. Although some reports suggest that the activation domain is dispensable in cell-culture models of hematopoiesis5,6, one study has shown that it is required for normal development in vivo7. Together, these findings indicate that loss of wildtype GATA1 constitutes one step in the pathogenesis of AMKL in Down syndrome.

PatentDOI
TL;DR: In this paper, compositions and methods for increasing the intrinsic fluorescence intensity of biomolecules and low quantum yield fluorophores are described. And methods for the identification of nucleic acids are also provided.

Journal ArticleDOI
TL;DR: The entire LEE of EPEC strain E2348/69 is sequenced and the final LEE sequence entry contains corrections to some of these previously reported genes and predicted proteins and changes the name of several previously described genes comprising the type III secretion system ofEPEC.
Abstract: Enteropathogenic Escherichia coli (EPEC) are an important aetiological agent in infant diarrhoea and the prototype for a family of pathogens exhibiting the unique virulence mechanism known as attaching and effacing (AE) (Nataro and Kaper, 1998). All genes necessary for AE are encoded on a 35 kb chromosomal pathogenicity island called the locus of enterocyte effacement (LEE), which contains genes encoding a type III secretion system, secreted proteins (Esp) and the adhesin intimin (McDaniel et al., 1995; McDaniel and Kaper, 1997). Study of the LEE will illuminate our understanding of the pathogenesis of EPEC and other AE pathogens and contribute to the growing body of knowledge about type III secretion systems and pathogenicity islands. We have recently sequenced the entire LEE of EPEC strain E2348/69 and describe below our initial analysis. Further details can be found in GenBank (accession number AF022236) and on the Molecular Microbiology Web site (http://www.blackwellscience.com/products/journals/mole.htm). The complete region was 35 624 bp with an average G þ C content of 38.36%, which is far below that of the E. coli chromosome (50.8%; Blattner et al., 1997), a pattern in keeping with many other pathogenicity islands (Hacker et al., 1997). The LEE contains 41 predicted open reading frames (ORFs) (of > 50 amino acids) arranged in at least five polycistronic operons, as predicted by the close spacing of co-directional genes. The LEE may be divided into at least three functional domains (Fig. 1): the central eae (encoding intimin), the region encoding the secreted Esp proteins and a large region encoding the type III secretion apparatus. Several LEE genes have been reported previously, and our final LEE sequence entry contains corrections to some of these previously reported genes and predicted proteins. Additionally, we have decided to adopt a standardized nomenclature (Bogdanove et al., 1996a; Yahr et al., 1997), which changes the name of several previously described genes comprising the type III secretion system of EPEC (Jarvis et al., 1995). Those genes homologous to Yersinia type III secretion (ysc) genes are referred to as esc (E. coli secretion) genes with the same suffix as the Yersinia homologue (e.g. sepA becomes escV, homologous with yscV; Table 1). Within the family of type III secretory genes, the LEE shares the highest level of predicted amino acid similarity and genetic organization with ssa genes from the SPI-2 pathogenicity island of Salmonella typhimurium (Shea et al., 1996). Genes that are not ysc homologues but are involved in type III secretion are named sep (secretion of E. coli proteins). The chaperone for the secretion of EspD is named cesD for chaperone for E. coli secreted protein D (Wainwright and Kaper, 1998). The remaining named genes, esp (E. coli secreted protein), eae (E. coli attaching and effacing) and orfU will retain their designations, and remaining ORFs are designated orf or rorf depending on the direction of transcription relative to eae. A brief description of selected LEE ORFs follows. More details can be found in Table 1, Fig. 1 and on the Molecular Microbiology home page (http://www.blackwell-science. com/products/journals/mole.htm. rOrf1 is similar to a protein of unknown function from E. coli K-12 and to a predicted lipoprotein that is encoded on the S. typhimurium virulence plasmid adjacent to rck (Heffernan et al., 1992), which has been shown to be important for virulence (Cirillo et al., 1996). rOrf2 is similar to the VirA protein of Shigella flexneri, a type III secreted protein that is involved in invasion and intercellular spreading (Uchiya et al., 1995). Secretion of rOrf2 has not been observed, and it is unclear what functions rOrf2 may have in EPEC, in which the role of invasion remains undefined. Molecular Microbiology (1998) 28(1), 1–4

Journal ArticleDOI
TL;DR: During routine office visits, neurologists failed to identify the presence of depression, anxiety, and fatigue more than half of the time and failed to recognize sleep disturbance in 40% of patients.

Journal ArticleDOI
TL;DR: Possible new criteria and class boundaries are proposed for additional biowaivers based on the underlying physiology of the gastrointestinal tract based on conservative criteria and potential biowaiver extension.
Abstract: The current BSC guidance issued by the FDA allows for biowaivers based on conservative criteria. Possible new criteria and class boundaries are proposed for additional biowaivers based on the underlying physiology of the gastrointestinal tract. The proposed changes in new class boundaries for solubility and permeability are as follows: 1. Narrow the required solubility pH range from 1.0-7.5 to 1.0-6.8. 2. Reduce the high permeability requirement from 90% to 85%. The following new criterion and potential biowaiver extension require more research: 1. Define a new intermediate permeability class boundary. 2. Allow biowaivers for highly soluble and intermediately permeable drugs in IR solid oral dosage forms with no less than 85% dissolved in 15 min in all physiologically relevant dissolution media, provided these IR products contain only known excipients that do not affect the oral drug absorption. The following areas require more extensive research: 1. Increase the dose volume for solubility classification to 500 mL. 2. Include bile salt in the solubility measurement. 3. Use the intrinsic dissolution method for solubility classification. 4. Define an intermediate solubility class for BCS Class II drugs. 5. Include surfactants in in vitro dissolution testing.

Journal ArticleDOI
TL;DR: This review covers recent developments in the cellular neurophysiology of retrograde signaling in the mammalian central nervous system and focuses on a group of molecules from different chemical classes that appear to act as retrograde messengers.

Journal ArticleDOI
01 Aug 2002-Nature
TL;DR: Data support an architectural role for the Rad50 coiled coils in forming metal-mediated bridging complexes between two DNA-binding heads that have appropriate lengths and conformational properties to link sister chromatids in homologous recombination and DNA ends in non-homologous end-joining.
Abstract: The Mre11 complex (Mre11 Rad50 Nbs1) is central to chromosomal maintenance and functions in homologous recombination, telomere maintenance and sister chromatid association. These functions all imply that the linked binding of two DNA substrates occurs, although the molecular basis for this process remains unknown. Here we present a 2.2 A crystal structure of the Rad50 coiled-coil region that reveals an unexpected dimer interface at the apex of the coiled coils in which pairs of conserved Cys-X-X-Cys motifs form interlocking hooks that bind one Zn(2+) ion. Biochemical, X-ray and electron microscopy data indicate that these hooks can join oppositely protruding Rad50 coiled-coil domains to form a flexible bridge of up to 1,200 A. This suggests a function for the long insertion in the Rad50 ABC-ATPase domain. The Rad50 hook is functional, because mutations in this motif confer radiation sensitivity in yeast and disrupt binding at the distant Mre11 nuclease interface. These data support an architectural role for the Rad50 coiled coils in forming metal-mediated bridging complexes between two DNA-binding heads. The resulting assemblies have appropriate lengths and conformational properties to link sister chromatids in homologous recombination and DNA ends in non-homologous end-joining.

Journal ArticleDOI
TL;DR: Pharmacological agents targeting specific KP enzymes can be used to normalize KP defects, show remarkable efficacy in animal models of central nervous system disorders, and offer novel therapeutic opportunities.
Abstract: Degradation of the essential amino acid tryptophan along the kynurenine pathway (KP) yields several neuroactive intermediates, including the free radical generator 3-hydroxykynurenine, the excitotoxic N-methyl-D-aspartate (NMDA) receptor agonist quinolinic acid, and the NMDA and alpha7 nicotinic acetylcholine receptor antagonist kynurenic acid. The ambient levels of these compounds are determined by several KP enzymes, which in the brain are preferentially localized in astrocytes and microglial cells. Normal fluctuations in the brain levels of neuroactive KP intermediates might modulate several neurotransmitter systems. Impairment of KP metabolism is functionally significant and occurs in a variety of diseases that affect the brain. Pharmacological agents targeting specific KP enzymes are now available to manipulate the concentration of neuroactive KP intermediates in the brain. These compounds can be used to normalize KP defects, show remarkable efficacy in animal models of central nervous system disorders, and offer novel therapeutic opportunities.

Journal ArticleDOI
TL;DR: It is demonstrated that any detectable decrease in renal function is associated with increased mortality and prolonged hospital stay, and suggests that therapeutic interventions which improve renal function might be beneficial.

Journal ArticleDOI
TL;DR: Titration of initial fluid therapy to a lower than normal SBP during active hemorrhage did not affect mortality in this study, and overall mortality was decreased overall mortality and the lack of differentiation between groups likely include improvements in diagnostic and therapeutic technology.
Abstract: Background Traditional fluid resuscitation strategy in the actively hemorrhaging trauma patient emphasizes maintenance of a normal systolic blood pressure (SBP). One human trial has demonstrated improved survival when fluid resuscitation is restricted, whereas numerous laboratory studies have report

Journal ArticleDOI
15 Jun 2002-Cancer
TL;DR: Cancer of the appendix is an uncommon disease that is rarely suspected rarely before surgery, and although several case series of these tumors have been published, little research has been anchored in population‐based data on cancer of the Appendix.
Abstract: BACKGROUND Cancer of the appendix is an uncommon disease that is rarely suspected rarely before surgery. Although several case series of these tumors have been published, little research has been anchored in population-based data on cancer of the appendix. METHODS This analysis included all actively followed cases of appendiceal neoplasms reported to the National Cancer Institute's Surveillance, Epidemiology and End-Results (SEER) program between 1973 and 1998. Tumors were classified as “colonic type” adenocarcinoma, mucinous adenocarcinoma, signet ring cell carcinoma, goblet cell carcinoid, and “malignant carcinoid” (SEER only collects data on carcinoids specifically classified as malignant). We compared incidence, overall survival and survival rates by extent of disease at diagnosis. RESULTS Between 1973 and 1998, 2117 appendiceal malignancies were reported to the SEER program, of which 1645 cases were included in the analysis. Age-adjusted incidence of cancer of the appendix was 0.12 cases per 1,000,000 people per year. Demographic characteristics of patients with goblet cell carcinoid tumors were midway between those of patients with malignant carcinoid and all types of adenocarcinomas. After controlling for age and extent of disease at diagnosis, the overall survival rate for patients diagnosed between 1983 and 1997 (n = 1061) was significantly worse for those with signet ring cell carcinoma than for those with any other tumor type (P < 0.01). In addition, overall survival rates were better for patients with malignant carcinoid (P = 0.01). CONCLUSIONS Demographic characteristics of patients with cancer of the appendix vary by histology. Except for signet ring cell carcinoma and malignant carcinoid, the extent of disease at time of diagnosis is a more important predictor of survival than histology. Cancer 2002;94:3307–12. © 2002 American Cancer Society. DOI 10.1002/cncr.10589

Journal ArticleDOI
TL;DR: Infections caused by parasites with 3 DHFR mutations and 2 DHPS mutations (the "quintuple mutant") were associated with sulfadoxine-pyrimethamine treatment failure but not with chlorproguanil-dapsone treatment failure.
Abstract: Molecular assays for monitoring sulfadoxine-pyrimethamine-resistant Plasmodium falciparum have not been implemented because of the genetic and statistical complexity of the parasite mutations that confer resistance and their relation to treatment outcomes. This study analyzed pretreatment dihydrofolate reductase (DHFR) and dihydropteroate synthase (DHPS) genotypes and treatment outcomes in a double-blind, placebo-controlled trial of sulfadoxine-pyrimethamine and chlorproguanil-dapsone treatment for uncomplicated P. falciparum malaria. Multiple logistic regression was used to identify mutations that were predictive of treatment failure and to identify interactions and confounding factors. Infections caused by parasites with 3 DHFR mutations and 2 DHPS mutations (the "quintuple mutant") were associated with sulfadoxine-pyrimethamine treatment failure but not with chlorproguanil-dapsone treatment failure. The presence of a single DHFR mutation (Arg-59) with a single DHPS mutation (Glu-540) accurately predicted the presence of the quintuple mutant. If this model is validated in other populations, it will finally be possible to use molecular markers for surveillance of antifolate-resistant P. falciparum malaria in Africa.

Journal ArticleDOI
TL;DR: A two‐component system regulated by quorum sensing that shares homology with Salmonella typhimurium PmrAB is described, which is named quorum Sensing E. coli regulator B and C (QseBC).
Abstract: Quorum sensing is a cell-to-cell signalling mechanism in which bacteria secrete hormone-like compounds called autoinducers. When these auto-inducers reach a certain threshold concentration, they interact with bacterial transcriptional regulators, thereby regulating gene expression. Enterohaemorrhagic Escherichia coli (EHEC) O157:H7 as well as E. coli K-12 produces the autoinducer-2 (AI-2), which is synthesized by the product of the luxS gene, and previous work from our laboratory has shown that genes encoding the EHEC type III secretion system were activated by quorum sensing. Recently, by hybridizing an E. coli K-12 gene array with cDNA synthesized from RNA extracted from EHEC strain 86-24 and its isogenic luxS mutant, we observed that other potential virulence-associated factors, such as genes encoding the expression and assembly of flagella, motility and chemotaxis, were also activated by quorum sensing. The array data also indicated that several genes encoding putative E. coli regulators were controlled by quorum sensing. In this report, we describe a two-component system regulated by quorum sensing that shares homology with Salmonella typhimurium PmrAB, which we have named quorum sensing E. coli regulator B and C (QseBC). The qseBC genes, previously identified only as open reading frames b3025 and b3026, are organized in an operon in the E. coli chromosome, with qseB encoding the response regulator and qseC the sensor kinase. We confirmed the regulation of qseBC by quorum sensing using qseB::lacZ transcriptional fusions and characterized the phenotypes of an isogenic qseC mutation in EHEC. This mutant expressed less flagellin and had reduced motility compared with the wild-type and complemented strains. Transcription of flhD, fliA, motA and fliC::lacZ fusions was decreased in the qseC mutant, suggesting that qseBC is a transcriptional regulator of flagella genes. A qseC mutant was also generated in E. coli K-12 strain MC1000 that showed the same phenotypes as the EHEC mutant, indicating that qseBC regulates flagella and motility by quorum sensing in both EHEC and K-12. QseBC activates transcription of flhDC, which is the master regulator for the flagella and motility genes and, in the absence of flhD, QseBC failed to activate the transcription of fliA. Motility of a luxS, but not of a qseC, mutant can be restored by providing AI-2 exogenously as preconditioned media, suggesting that the qseC mutant is unable to respond to AI-2. However, QseC has no effect on the expression of other quorum sensing-controlled genes such as those encoding for the type III secretion system. These data indicate that QseBC is one component of the quorum-sensing regulatory cascade in both EHEC and K-12 that is involved in the regulation of flagella and motility genes, but that additional regulators in this cascade remain to be characterized.

Journal ArticleDOI
TL;DR: The results suggest that surfactants can inhibit multiple transporters but that changes in membrane fluidity may not be a generalized mechanism to reduce transporter activity.

Journal ArticleDOI
TL;DR: A mathematical model is developed to evaluate factors affecting the prevalence of human commensal AR bacteria that cause opportunistic infections and suggests that AAU hastens the appearance of AR bacteria in humans.
Abstract: Antibiotic use is known to promote the development of antibiotic resistance, but substantial controversy exists about the impact of agricultural antibiotic use (AAU) on the subsequent emergence of antibiotic-resistant bacteria among humans. AAU for animal growth promotion or for treatment or control of animal diseases generates reservoirs of antibiotic-resistant (AR) bacteria that contaminate animal food products. Mathematical models are an important tool for understanding the potential medical consequences of this increased exposure. We have developed a mathematical model to evaluate factors affecting the prevalence of human commensal AR bacteria that cause opportunistic infections (e.g., enterococci). Our analysis suggests that AAU hastens the appearance of AR bacteria in humans. Our model indicates that the greatest impact occurs very early in the emergence of resistance, when AR bacteria are rare, possibly below the detection limits of current surveillance methods.

Journal ArticleDOI
TL;DR: A meta-analysis of all randomized, placebo-controlled trials of antiresorptive agents conducted in postmenopausal women with osteoporosis demonstrated that larger increases in BMD at both the spine and hip and larger reductions in both formation and resorption BCM are associated with greater reductions in the risk of nonvertebral fractures.
Abstract: Some, but not all, antiresorptive agents have been shown to reduce the risk of nonvertebral fractures. Agents that significantly reduced nonvertebral fracture risk also appear to produce larger mean increases in bone mineral density (BMD) and reductions in biochemical markers (BCM) of bone turnover, compared with other agents. To examine the extent to which increases in BMD and reductions in BCM during antiresorptive therapy are associated with reductions in risk of nonvertebral fractures, we performed a meta-analysis of all randomized, placebo-controlled trials of antiresorptive agents conducted in postmenopausal women with osteoporosis (i.e. prior vertebral fracture or low BMD) with available relevant data. A total of 18 such trials with usable data were identified, including a total of 2,415 women with incident nonvertebral fractures over 69,369 women-years of follow-up. Poisson regression was used to estimate the association between changes in BMD or BCM during the first year and overall reductions in risk of nonvertebral fractures (vs. the placebo group) across all trials. Larger increases in BMD and larger reductions in BCM were significantly associated with greater reductions in nonvertebral fracture risk. For example, each 1% increase in spine BMD at 1 yr was associated with an 8% reduction in nonvertebral fracture risk (P = 0.02). Mean BMD changes at the hip were smaller than at the spine, but the predicted net effect on fracture risk was the same; an agent that increases spine BMD by 6% at 1 yr reduces nonvertebral fracture risk by about 39%, and an agent that increases hip BMD by 3% at 1 yr reduces nonvertebral fracture risk by about 46%. The results also predict that a 70% reduction in resorption BCM would reduce risk by 40%, and a 50% reduction in formation BCM would reduce risk by 44%. It appears that either BMD or BCM changes are able to explain the effect of treatment, because a separate variable for treatment was not independently significant in any models. These data demonstrate that larger increases in BMD at both the spine and hip and larger reductions in both formation and resorption BCM are associated with greater reductions in the risk of nonvertebral fractures. Antiresorptive agents that do not produce large increases in BMD or large reductions in BCM do not appear to and would not be expected to decrease the risk of nonvertebral fractures.