Showing papers by "University of Maryland, Baltimore published in 2005"

A haplotype map of the human genome

Abstract: Inherited genetic variation has a critical but as yet largely uncharacterized role in human disease. Here we report a public database of common variation in the human genome: more than one million single nucleotide polymorphisms (SNPs) for which accurate and complete genotypes have been obtained in 269 DNA samples from four populations, including ten 500-kilobase regions in which essentially all information about common DNA variation has been extracted. These data document the generality of recombination hotspots, a block-like structure of linkage disequilibrium and low haplotype diversity, leading to substantial correlations of SNPs with many of their neighbours. We show how the HapMap resource can guide the design and analysis of genetic association studies, shed light on structural variation and recombination, and identify loci that may have been subject to natural selection during human evolution.

Infectious Diseases Society of America Guidelines for the Diagnosis and Treatment of Asymptomatic Bacteriuria in Adults

Abstract: 1. The diagnosis of asymptomatic bacteriuria should be based on results of culture of a urine specimen collected in a manner that minimizes contamination (A-II) (table 1). • For asymptomatic women, bacteriuria is defined as 2 consecutive voided urine specimens with isolation of the same bacterial strain in quantitative counts 10 cfu/mL (B-II). • A single, clean-catch voided urine specimen with 1 bacterial species isolated in a quantitative count 10 cfu/mL identifies bacteriuria in men (BIII). • A single catheterized urine specimen with 1 bacterial species isolated in a quantitative count 10 cfu/mL identifies bacteriuria in women or men (A-II). 2. Pyuria accompanying asymptomatic bacteriuria is not an indication for antimicrobial treatment (A-II). 3. Pregnant women should be screened for bacteriuria by urine culture at least once in early pregnancy, and they should be treated if the results are positive (A-I). • The duration of antimicrobial therapy should be

Cystatin C and the risk of death and cardiovascular events among elderly persons.

Abstract: Background Cystatin C is a serum measure of renal function that appears to be independent of age, sex, and lean muscle mass. We compared creatinine and cystatin C levels as predictors of mortality from cardiovascular causes and from all causes in the Cardiovascular Health Study, a cohort study of elderly persons living in the community. Methods Creatinine and cystatin C were measured in serum samples collected from 4637 participants at the study visit in 1992 or 1993; follow-up continued until June 30, 2001. For each measure, the study population was divided into quintiles, with the fifth quintile subdivided into thirds (designated 5a, 5b, and 5c). Results Higher cystatin C levels were directly associated, in a dose–response manner, with a higher risk of death from all causes. As compared with the first quintile, the hazard ratios (and 95 percent confidence intervals) for death were as follows: second quintile, 1.08 (0.86 to 1.35); third quintile, 1.23 (1.00 to 1.53); fourth quintile, 1.34 (1.09 to 1.66);...

Polyomavirus-Associated Nephropathy in Renal Transplantation: Interdisciplinary Analyses and Recommendations

Abstract: Polyomavirus-associated nephropathy (PVAN) is an emerging cause of kidney transplant failure affecting 1-10% of patients. As uncertainty exists regarding risk factors, diagnosis, and intervention, an independent panel of experts reviewed the currently available evidence and prepared this report. Most cases of PVAN are elicited by BK virus (BKV) in the context of intense immunosuppression. No specific immunosuppressive drug is exclusively associated with PVAN, but most cases reported to date arise while the patient is on triple immunosuppressive combinations, often comprising tacrolimus and/or mycophenolate mofetil plus corticosteroids. Immunologic control of polyomavirus replication can be achieved by reducing, switching, and/or discontinuing components of the immunosuppressive regimen, but the individual's risk of rejection should be considered. The success rate of this intervention is increased with earlier diagnosis. Therefore, it is recommended that all renal transplant recipients should be screened for BKV replication in the urine: 1) every three months during the first two years posttransplant; 2) when allograft dysfunction is noted; and 3) when allograft biopsy is performed. A positive screening result should be confirmed in <4 weeks and assessed by quantitative assays (e.g. BKV DNA or RNA load in plasma or urine). Definitive diagnosis of PVAN requires allograft biopsy. If PVAN and concurrent acute rejection is diagnosed, antirejection treatment should be considered, coupled with subsequently reducing immunosuppression. The antiviral cidofovir is not approved for PVAN, but investigational use at low doses (0.25-0.33 mg/kg intravenously biweekly) without probenicid should be considered for refractory cases. Retransplantation after renal allograft loss to PVAN remains a treatment option for patients clearing polyomavirus replication.

An astrocytic basis of epilepsy

Abstract: Hypersynchronous neuronal firing is a hallmark of epilepsy, but the mechanisms underlying simultaneous activation of multiple neurons remains unknown Epileptic discharges are in part initiated by a local depolarization shift that drives groups of neurons into synchronous bursting In an attempt to define the cellular basis for hypersynchronous bursting activity, we studied the occurrence of paroxysmal depolarization shifts after suppressing synaptic activity using tetrodotoxin (TTX) and voltage-gated Ca2+ channel blockers Here we report that paroxysmal depolarization shifts can be initiated by release of glutamate from extrasynaptic sources or by photolysis of caged Ca2+ in astrocytes Two-photon imaging of live exposed cortex showed that several antiepileptic agents, including valproate, gabapentin and phenytoin, reduced the ability of astrocytes to transmit Ca2+ signaling Our results show an unanticipated key role for astrocytes in seizure activity As such, these findings identify astrocytes as a proximal target for the treatment of epileptic disorders

Placebo Effects Mediated by Endogenous Opioid Activity on μ-Opioid Receptors

Abstract: Reductions in pain ratings when administered a placebo with expected analgesic properties have been described and hypothesized to be mediated by the pain-suppressive endogenous opioid system. Using molecular imaging techniques, we directly examined the activity of the endogenous opioid system on μ-opioid receptors in humans in sustained pain with and without the administration of a placebo. Significant placebo-induced activation of μ-opioid receptor-mediated neurotransmission was observed in both higher-order and sub-cortical brain regions, which included the pregenual and subgenual rostral anterior cingulate, the dorsolateral prefrontal cortex, the insular cortex, and the nucleus accumbens. Regional activations were paralleled by lower ratings of pain intensity, reductions in its sensory and affective qualities, and in the negative emotional state of the volunteers. These data demonstrate that cognitive factors (e.g., expectation of pain relief) are capable of modulating physical and emotional states through the site-specific activation of μ-opioid receptor signaling in the human brain.

A scale-dependent Lagrangian dynamic model for large eddy simulation of complex turbulent flows

Abstract: A scale-dependent dynamic subgrid model based on Lagrangian time averaging is proposed and tested in large eddy simulations (LES) of high-Reynolds number boundary layer flows over homogeneous and heterogeneous rough surfaces. The model is based on the Lagrangian dynamic Smagorinsky model in which required averages are accumulated in time, following fluid trajectories of the resolved velocity field. The model allows for scale dependence of the coefficient by including a second test-filtering operation to determine how the coefficient changes as a function of scale. The model also uses the empirical observation that when scale dependence occurs (such as when the filter scale approaches the limits of the inertial range), the classic dynamic model yields the coefficient value appropriate for the test-filter scale. Validation tests in LES of high Reynolds number, rough wall, boundary layer flow are performed at various resolutions. Results are compared with other eddy-viscosity subgrid-scale models. Unlike the...

The relationships between parenting stress, parenting behaviour and preschoolers' social competence and behaviour problems in the classroom

Abstract: Young children develop social and emotional competence through interactions with others in the two major contexts in which they spend time: home and preschool. This study examined whether parenting stress in the home context is related to the children's behaviour while in preschool. Previous research has suggested that parenting stress negatively influences parenting behaviour, which in turn has been shown to impact children's development. This study examined the direct relationship between parenting stress and children's behaviour in two types of preschool programmes: private day care centres and Head Start. Parenting stress was significantly related to teacher ratings of social competence, internalizing behaviours, and externalizing behaviours, and the effects of parenting behaviour do not appear to mediate this relationship. Parenting stress was most strongly related to children's social competence. Parents' reports of expectations for their child's behaviour appear to weakly moderate the relationship between externalizing behaviour and parenting stress. This study suggests that examination of a parent's level of stress, in addition to parenting practices, may be important in research and interventions with preschool children's behaviour and social competence. Copyright © 2005 John Wiley & Sons, Ltd.

A new tool to assess treatment fidelity and evaluation of treatment fidelity across 10 years of health behavior research

Abstract: A. Bellg, B. Borrelli, et al. (2004) previously developed a framework that consisted of strategies to enhance treatment fidelity of health behavior interventions. The present study used this framework to (a) develop a measure of treatment fidelity and (b) use the measure to evaluate treatment fidelity in articles published in 5 journals over 10 years. Three hundred forty-two articles met inclusion criteria; 22% reported strategies to maintain provider skills, 27% reported checking adherence to protocol, 35% reported using a treatment manual, 54% reported using none of these strategies, and 12% reported using all 3 strategies. The mean proportion adherence to treatment fidelity strategies was .55; 15.5% of articles achieved greater than or equal to .80. This tool may be useful for researchers, grant reviewers, and editors planning and evaluating trials.

Hip Fracture in Women without Osteoporosis

Abstract: The proportion of fractures that occur in women without osteoporosis has not been fully described, and the characteristics of nonosteoporotic women who fracture are not well understood. We measured total hip bone mineral density (BMD) and baseline characteristics including physical activity, falls, and strength for 8065 women aged 65 yr or older participating in the Study of Osteoporotic Fractures and then followed these women for hip fracture for up to 5 yr after BMD measurement. Among all participants, 17% had osteoporosis (total hip BMD T-score < or = -2.5). Of the 243 women with incident hip fracture, 54% were not osteoporotic at start of follow-up. Nonosteoporotic women who fractured were less likely than osteoporotic women with fracture to have baseline characteristics associated with frailty. Nevertheless, among nonosteoporotic participants, several characteristics increased fracture risk, including advancing age, lack of exercise in the last year, reduced visual contrast sensitivity, falls in the last year, prevalent vertebral fracture, and lower total hip BMD. These findings call attention to the many older women who suffer hip fracture but do not have particularly low antecedent BMD measures and help begin to identify risk factors associated with higher bone density levels.

Scientific and Consumer Models of Recovery in Schizophrenia: Concordance, Contrasts, and Implications

Abstract: Schizophrenia has traditionally been viewed as a chronic condition with a very pessimistic outlook, but that assumption may not be valid. There has been a growing consumer movement among people with schizophrenia that has challenged both the traditional perspective on the course of illness and the associated assumptions about the possibility of people with the illness living a productive and satisfying life. This new conception of the illness is supported by long-term studies that suggest that as much as 50% of people with the illness have good outcomes. There has also been a change in political and public health perspectives of the illness, stimulated in part by the President's New Freedom Commission on Mental Health. The purpose of this article is to provide an overview of some key themes about the recovery concept, as applied to schizophrenia. The article will address 3 questions: (1) What is recovery? (2) Is recovery possible? and (3) What are the implications of a recovery model for a scientific approach to treatment (ie, the use of evidence-based practices)? Scientific and consumer models of recovery are described, and commonalities and differences are discussed. Priorities for future research are suggested.

Meniscal tear and extrusion are strongly associated with progression of symptomatic knee osteoarthritis as assessed by quantitative magnetic resonance imaging

Abstract: Background: The relation between knee meniscal structural damage and cartilage degradation is plausible but not yet clearly proven. Objectives: To quantitate the cartilage volume changes in knee osteoarthritis using magnetic resonance imaging (MRI), and determine whether meniscal alteration predicts cartilage volume loss over time. Methods: 32 patients meeting ACR criteria for symptomatic knee osteoarthritis were studied. MRI knee acquisitions were done every six months for two years. The cartilage volumes of different knee regions were measured. Three indices of structural change in the medial and lateral menisci were evaluated—degeneration, tear, and extrusion—using a semiquantitative scale. Results: 24 patients (75%) had mild to moderate or severe meniscal damage (tear or extrusion) at baseline. A highly significant difference in global cartilage volume loss was observed between severe medial meniscal tear and absence of tear (mean (SD), –10.1 (2.1)% v –5.1 (2.4)%, p = 0.002). An even greater difference was found between the medial meniscal changes and medial compartment cartilage volume loss (–14.3 (3.0)% in the presence of severe tear v –6.3 (2.7)% in the absence of tear; p<0.0001). Similarly, a major difference was found between the presence of a medial meniscal extrusion and loss of medial compartment cartilage volume (–15.4 (4.1)% in the presence of extrusion v –4.5 (1.7)% with no extrusion; p<0.001). Conclusions: Meniscal tear and extrusion appear to be associated with progression of symptomatic knee osteoarthritis.

Distinct epigenetic changes in the stromal cells of breast cancers.

Abstract: Increasing evidence suggests that changes in the cellular microenvironment contribute to tumorigenesis, but the molecular basis of these alterations is not well understood. Although epigenetic modifications of the neoplastic cells in tumors have been firmly implicated in tumorigenesis, it is not known whether epigenetic modifications occur in the non-neoplastic stromal cells. To address this question in an unbiased and genome-wide manner, we developed a new method, methylation-specific digital karyotyping, and applied it to epithelial and myoepithelial cells, stromal fibroblasts from normal breast tissue, and in situ and invasive breast carcinomas. Our analyses showed that distinct epigenetic alterations occur in all three cell types during breast tumorigenesis in a tumor stage- and cell type-specific manner, suggesting that epigenetic changes have a role in the maintenance of the abnormal cellular microenvironment in breast cancer.

Treadmill Exercise Rehabilitation Improves Ambulatory Function and Cardiovascular Fitness in Patients With Chronic Stroke A Randomized, Controlled Trial

Abstract: Background and Purpose— Physical inactivity propagates disability after stroke through physical deconditioning and learned nonuse. We investigated whether treadmill aerobic training (T-AEX) is more effective than conventional rehabilitation to improve ambulatory function and cardiovascular fitness in patients with chronic stroke. Methods— Sixty-one adults with chronic hemiparetic gait after ischemic stroke (>6 months) were randomized to 6 months (3×/week) progressive T-AEX or a reference rehabilitation program of stretching plus low-intensity walking (R-CONTROL). Peak exercise capacity (Vo2 peak), o2 consumption during submaximal effort walking (economy of gait), timed walks, Walking Impairment Questionnaire (WIQ), and Rivermead Mobility Index (RMI) were measured before and after 3 and 6 months of training. Results— Twenty-five patients completed T-AEX and 20 completed R-CONTROL. Only T-AEX increased cardiovascular fitness (17% versus 3%, δ% T-AEX versus R-CONTROL, P<0.005). Group-by-time analyses reveale...

The Exopolysaccharide Alginate Protects Pseudomonas aeruginosa Biofilm Bacteria from IFN-γ-Mediated Macrophage Killing

Abstract: The ability of Pseudomonas aeruginosa to form biofilms and cause chronic infections in the lungs of cystic fibrosis patients is well documented. Numerous studies have revealed that P. aeruginosa biofilms are highly refractory to antibiotics. However, dramatically fewer studies have addressed P. aeruginosa biofilm resistance to the host’s immune system. In planktonic, unattached (nonbiofilm) P. aeruginosa, the exopolysaccharide alginate provides protection against a variety of host factors yet the role of alginate in protection of biofilm bacteria is unclear. To address this issue, we tested wild-type strains PAO1, PA14, the mucoid cystic fibrosis isolate, FRD1 (mucA22+), and the respective isogenic mutants which lacked the ability to produce alginate, for their susceptibility to human leukocytes in the presence and absence of IFN-γ. Human leukocytes, in the presence of recombinant human IFN-γ, killed biofilm bacteria lacking alginate after a 4-h challenge at 37°C. Bacterial killing was dependent on the presence of IFN-γ. Killing of the alginate-negative biofilm bacteria was mediated through mononuclear cell phagocytosis since treatment with cytochalasin B, which prevents actin polymerization, inhibited leukocyte-specific bacterial killing. By direct microscopic observation, phagocytosis of alginate-negative biofilm bacteria was significantly increased in the presence of IFN-γ vs all other treatments. Addition of exogenous, purified alginate to the alginate-negative biofilms restored resistance to human leukocyte killing. Our results suggest that although alginate may not play a significant role in bacterial attachment, biofilm development, and formation, it may play an important role in protecting mucoid P. aeruginosa biofilm bacteria from the human immune system.

Meta-Analysis: Acupuncture for Low Back Pain

Abstract: According to the evidence provided by 33 randomized trials, needle acupuncture provides better short-term relief for chronic low back pain than sham acupuncture or no treatment. The evidence about ...

Mechanisms of Resistance of Malaria Parasites to Antifolates

Abstract: Antifolate antimalarial drugs interfere with folate metabolism, a pathway essential to malaria parasite survival. This class of drugs includes effective causal prophylactic and therapeutic agents, some of which act synergistically when used in combination. Unfortunately, the antifolates have proven susceptible to resistance in the malaria parasite. Resistance is caused by point mutations in dihydrofolate reductase and dihydropteroate synthase, the two key enzymes in the folate biosynthetic pathway that are targeted by the antifolates. Resistance to these drugs arises relatively rapidly in response to drug pressure and is now common worldwide. Nevertheless, antifolate drugs remain first-line agents in several sub-Saharan African countries where chloroquine resistance is widespread, at least partially because they remain the only affordable, effective alternative. New antifolate combinations that are more effective against resistant parasites are being developed and in one case, recently introduced into use. Combining these antifolates with drugs that act on different targets in the parasite should greatly enhance their effectiveness as well as deter the development of resistance. Molecular epidemiological techniques for monitoring parasite drug resistance may contribute to development of strategies for prolonging the useful therapeutic life of this important class of drugs.

Targeted inactivation of hepatic Abca1 causes profound hypoalphalipoproteinemia and kidney hypercatabolism of apoA-I

Abstract: Patients with Tangier disease exhibit extremely low plasma HDL concentrations resulting from mutations in the ATP-binding cassette, sub-family A, member 1 (ABCA1) protein. ABCA1 controls the rate-limiting step in HDL particle assembly by mediating efflux of cholesterol and phospholipid from cells to lipid-free apoA-I, which forms nascent HDL particles. ABCA1 is widely expressed; however, the specific tissues involved in HDL biogenesis are unknown. To determine the role of the liver in HDL biogenesis, we generated mice with targeted deletion of the second nucleotide-binding domain of Abca1 in liver only (Abca1(-L/-L)). Abca1(-L/-L) mice had total plasma and HDL cholesterol concentrations that were 19% and 17% those of wild-type littermates, respectively. In vivo catabolism of HDL apoA-I from wild-type mice or human lipid-free apoA-I was 2-fold higher in Abca1(-L/-L) mice compared with controls due to a 2-fold increase in the catabolism of apoA-I by the kidney, with no change in liver catabolism. We conclude that in chow-fed mice, the liver is the single most important source of plasma HDL. Furthermore, hepatic, but not extrahepatic, Abca1 is critical in maintaining the circulation of mature HDL particles by direct lipidation of hepatic lipid-poor apoA-I, slowing its catabolism by the kidney and prolonging its plasma residence time.

Wnt signaling through Dishevelled, Rac and JNK regulates dendritic development

Abstract: Dendritic arborization is required for proper neuronal connectivity. Rho GTPases have been implicated in the regulation of dendrite development. However, the signaling pathways that impinge on these molecular switches remain poorly understood. Here we show that Wnt7b, which is expressed in the mouse hippocampus, increases dendritic branching in cultured hippocampal neurons. This effect is mimicked by the expression of Dishevelled (Dvl) and is blocked by Sfrp1, a secreted Wnt antagonist. Consistent with these findings, hippocampal neurons from mice lacking Dvl1 show reduced dendritic arborization. Activation of the canonical Wnt-Gsk3β pathway does not affect dendritic development. In contrast, Wnt7b and Dvl activate Rac and JNK in hippocampal neurons. Dominant-negative Rac, dominant-negative JNK or inhibition of JNK blocks Dvl-mediated dendritic growth. These findings demonstrate a new function for the non-canonical Wnt pathway in dendrite development and identify Dvl as a regulator of Rho GTPases and JNK during dendritic morphogenesis.

A multilevel analysis of sociability, usability, and community dynamics in an online health community

Abstract: The aim of this research is to develop an in-depth understanding of the dynamics of online group interaction and the relationship between the participation in an online community and an individual's off-line life. The 2h-year study of a thriving online health support community (Bob's ACL WWWBoard) used a broad fieldwork approach, guided by the ethnographic research techniques of observation, interviewing, and archival research in combination with analysis of the group's dynamics during a one-week period. Research tools from the social sciences were used to develop a thick, rich description of the group. The significant findings of this study include: dependable and reliable technology is more important than state-of-the-art technology in this community; strong community development exists despite little differentiation of the community space provided by the software; members reported that participation in the community positively influenced their offline lives; strong group norms of support and reciprocity made externally-driven governance unnecessary; tools used to assess group dynamics in face-to-face groups provide meaningful information about online group dynamics; and, membership patterns in the community and strong subgroups actively contributed to the community's stability and vitality.

Future Biomarkers for Detection of Ischemia and Risk Stratification in Acute Coronary Syndrome

Abstract: Background: Evaluation of patients who present to the hospital with a complaint of chest pain or other signs or symptoms suggestive of acute coronary syndrome (ACS) is time-consuming, expensive, and problematic. Recent investigations have indicated that increases in biomarkers upstream from biomarkers of necrosis (cardiac troponins I and T), such as inflammatory cytokines, cellular adhesion molecules, acute-phase reactants, plaque destabilization and rupture biomarkers, biomarkers of ischemia, and biomarkers of myocardial stretch may provide earlier assessment of overall patient risk and aid in identifying patients with higher risk of an adverse event. Approach and Content: The purpose of this review is to provide an overview of the pathophysiology and clinical and analytical characteristics of several biomarkers that may have potential clinical utility to identify ACS patients. These biomarkers (myeloperoxidase, metalloproteinase-9, soluble CD40 ligand, pregnancy-associated plasma protein A, choline, ischemia-modified albumin, unbound free fatty acids, glycogen phosphorylase isoenzyme BB, and placental growth factor) have demonstrated promise and need to be more thoroughly evaluated for commercial development for implementation into routine clinical and laboratory practice. Summary: Specifications that have been addressed for cardiac troponins and natriuretic peptides will need to be addressed with the same scrutiny for the biomarkers discussed in this review. They include validating analytical imprecision and detection limits, calibrator characterization, assay specificity and standardization, preanalytical issues, and appropriate reference interval studies. Crossing boundaries from research to clinical application will require replication in multiple settings and experimental evidence supporting a pathophysiologic role and, ideally, interventional trials demonstrating that monitoring single or multiple biomarkers improves outcomes.

Mechanisms of Disease: the role of intestinal barrier function in the pathogenesis of gastrointestinal autoimmune diseases

Abstract: SUMMARY The primary functions of the gastrointestinal tract have traditionally been perceived to be limited to the digestion and absorption of nutrients and electrolytes, and to water homeostasis. A more attentive analysis of the anatomic and functional arrangement of the gastrointestinal tract, however, suggests that another extremely important function of this organ is its ability to regulate the trafficking of macromolecules between the environment and the host through a barrier mechanism. Together with the gut-associated lymphoid tissue and the neuroendocrine network, the intestinal epithelial barrier, with its intercellular tight junctions, controls the equilibrium between tolerance and immunity to nonself-antigens. When the finely tuned trafficking of macromolecules is dysregulated in genetically susceptible individuals, both intestinal and extraintestinal autoimmune disorders can occur. This new paradigm subverts traditional theories underlying the development of autoimmunity, which are based on molecular mimicry and/or the bystander effect, and suggests that the autoimmune process can be arrested if the interplay between genes and environmental triggers is prevented by re-establishing intestinal barrier function. Understanding the role of the intestinal barrier in the pathogenesis of gastrointestinal disease is an area of translational research that encompasses many fields and is currently receiving a great deal of attention. This review is timely given the increased interest in the role of a ‘leaky gut’ in the pathogenesis of gastrointestinal diseases and the advent of novel treatment strategies, such as the use of probiotics.