Showing papers by "VA Palo Alto Healthcare System published in 2006"
TL;DR: A novel class of methylated H3K4 effector domains—the PHD domains of the ING (for inhibitor of growth) family of tumour suppressor proteins—are identified and established a pivotal role for trimethylation of H 3K4 in gene repression and, potentially, tumour suppressing mechanisms.
Abstract: Dynamic regulation of diverse nuclear processes is intimately linked to covalent modifications of chromatin. Much attention has focused on methylation at lysine 4 of histone H3 (H3K4), owing to its association with euchromatic genomic regions. H3K4 can be mono-, di- or tri-methylated. Trimethylated H3K4 (H3K4me3) is preferentially detected at active genes, and is proposed to promote gene expression through recognition by transcription-activating effector molecules. Here we identify a novel class of methylated H3K4 effector domains--the PHD domains of the ING (for inhibitor of growth) family of tumour suppressor proteins. The ING PHD domains are specific and highly robust binding modules for H3K4me3 and H3K4me2. ING2, a native subunit of a repressive mSin3a-HDAC1 histone deacetylase complex, binds with high affinity to the trimethylated species. In response to DNA damage, recognition of H3K4me3 by the ING2 PHD domain stabilizes the mSin3a-HDAC1 complex at the promoters of proliferation genes. This pathway constitutes a new mechanism by which H3K4me3 functions in active gene repression. Furthermore, ING2 modulates cellular responses to genotoxic insults, and these functions are critically dependent on ING2 interaction with H3K4me3. Together, our findings establish a pivotal role for trimethylation of H3K4 in gene repression and, potentially, tumour suppressor mechanisms.
955 citations
TL;DR: Unravelling distinct contributions to the aged phenotype will be critical to the success of any therapeutic application of stem cells in the emerging field of regenerative medicine with respect to tissue injury, degenerative diseases or normal functional declines that accompany ageing.
Abstract: Adult stem cells reside in most mammalian tissues, but the extent to which they contribute to normal homeostasis and repair varies widely. There is an overall decline in tissue regenerative potential with age, and the question arises as to whether this is due to the intrinsic ageing of stem cells or, rather, to the impairment of stem-cell function in the aged tissue environment. Unravelling these distinct contributions to the aged phenotype will be critical to the success of any therapeutic application of stem cells in the emerging field of regenerative medicine with respect to tissue injury, degenerative diseases or normal functional declines that accompany ageing.
683 citations
TL;DR: Simultaneous p63 and p53 knockdown rescued the cell proliferation defect of p63 knockdown alone but failed to restore differentiation, suggesting that defects in epidermal proliferation and differentiation are mediated via p53-dependent and -independent mechanisms, respectively.
Abstract: p63 is a multi-isoform p53 family member required for epidermal development Contrasting roles for p63 in either the initial commitment to the stratified epithelial cell fate or in stem cell-based self-renewal have been proposed To investigate p63 function in a post-developmental context, we used siRNAs directed against p63 to down-regulate p63 expression in regenerating human epidermis Loss of p63 resulted in severe tissue hypoplasia and inhibited both stratification and differentiation in a cell-autonomous manner Although p63-deficient cells exhibited hypoproliferation, differentiation defects were not due to tissue hypoplasia Simultaneous p63 and p53 knockdown rescued the cell proliferation defect of p63 knockdown alone but failed to restore differentiation, suggesting that defects in epidermal proliferation and differentiation are mediated via p53-dependent and -independent mechanisms, respectively Furthermore, ΔNp63 isoforms are the main mediators of p63 effects, although TAp63 isoforms may contribute to late differentiation These data indicate that p63 is required for both the proliferative and differentiation potential of developmentally mature keratinocytes
455 citations
TL;DR: It is suggested that a relatively small group of muscles provides most of the forward progression and support needed for normal walking, and that walking dynamics are influenced by non-sagittal muscles, such as the gluteus medius, even though walking is primarily a sagittal-plane task.
307 citations
TL;DR: The findings identify age, type of vaccine, and prevaccination levels of immune reactivity to influenza A virus as factors significantly associated with the magnitude of cellular immune responses to influenza vaccines.
Abstract: The patterns of cellular immune responses induced by live attenuated influenza vaccine (LAIV) versus those of the trivalent inactivated influenza vaccine (TIV) have not been studied extensively, especially in children. The goals of this study were to evaluate the effects of TIV and LAIV immunization on cellular immunity to live influenza A virus in children and adults and to explore factors associated with variations in responses to influenza vaccines among individuals. A gamma interferon (IFN-γ) flow cytometry assay was used to measure IFN-γ-producing (IFN-γ+) NK and T cells in peripheral blood mononuclear cell cultures stimulated with a live influenza A virus strain before and after LAIV or TIV immunization of children and adults. The mean percentages of influenza A virus-specific IFN-γ+ CD4 and CD8 T cells increased significantly after LAIV, but not TIV, immunization in children aged 5 to 9 years. No increases in the mean levels of influenza A virus-reactive IFN-γ+ T cells and NK cells were observed in adults given LAIV or TIV. TIV induced a significant increase in influenza A virus-reactive T cells in 6-month- to 4-year-old children; LAIV was not evaluated in this age group. The postvaccination changes (n-fold) in the percentages of influenza A virus-reactive IFN-γ+ T and NK cells in adults were highly variable and correlated inversely with the prevaccination percentages, in particular with that of the CD56dim NK cell subset. In conclusion, our findings identify age, type of vaccine, and prevaccination levels of immune reactivity to influenza A virus as factors significantly associated with the magnitude of cellular immune responses to influenza vaccines.
300 citations
01 Jan 2006
TL;DR: In this paper, the authors describe a conceptual framework based on Moos' transactional model that encompasses the role of culture in stress and coping, and illustrate how culture serves as a pervasive context for the stress-and-coping paradigm.
Abstract: The field of stress and coping emerged more than three decades ago from the recognition of the dynamic interaction between person and environment (Lazarus & Folkman, 1984; Moos, 2002). Over the years, researchers developed a system of objectifying and quantifying people’s environment, such as counting the number of major life events or daily hassles that occurred in the past month. Unfortunately, this system of measuring the environment resulted in acontextualizing the stress and coping research paradigm as it does not give much consideration to the meaning of the events that occur in an idiosyncratic life context. In recent years, the field has been trying to introduce more realism to stress and coping research, as the acontextual research of the last two decades yielded few solid findings that made a difference in people’s lives (Somerfield & McCrae, 2000). One of the most important neglected contexts is culture. We believe that culture is a fundamental context that helps to shape both the individual and the environment. There have been growing efforts to examine cross-cultural variations in stress and coping, but these efforts are fragmented and primarily descriptive, and usually lack an overarching conceptual framework. The aim of our overview is to help shape future research to address the generalizability of current models of stress and coping across cultural and ethnic groups. Here we describe a conceptual framework based on Moos’ transactional model (1984; 2002) that encompasses the role of culture in stress and coping. Using this conceptual framework, we illustrate how culture serves as a pervasive context for the stress and coping paradigm, and present some empirical evidence on this issue. We conclude by addressing several key issues and assumptions of the current stress and coping paradigm that may have contributed to conceptual confusion and slowed the progress of cross-cultural investigations, and we offer ways to solve these problems.
295 citations
TL;DR: A low KCCQ score is an independent predictor of poor prognosis in outpatients with heart failure, and remained significantly associated with survival free of HF hospitalization.
271 citations
TL;DR: Populations with serious health needs and those facing significant barriers in accessing health care in traditional settings turn to the Internet for health information.
Abstract: Objective. To determine what types of consumers use the Internet as a source of health information.
Data Sources. A survey of consumer use of the Internet for health information conducted during December 2001 and January 2002.
Study Design. We estimated multivariate regression models to test hypotheses regarding the characteristics of consumers that affect information seeking behavior.
Data Collection. Respondents were randomly sampled from an Internet-enabled panel of over 60,000 households. Our survey was sent to 12,878 panel members, and 69.4 percent of surveyed panel members responded. We collected information about respondents' use of the Internet to search for health information and to communicate about health care with others using the Internet or e-mail within the last year.
Principal Findings. Individuals with reported chronic conditions were more likely than those without to search for health information on the Internet. The uninsured, particularly those with a reported chronic condition, were more likely than the privately insured to search. Individuals with longer travel times for their usual source of care were more likely to use the Internet for health-related communication than those with shorter travel times.
Conclusions. Populations with serious health needs and those facing significant barriers in accessing health care in traditional settings turn to the Internet for health information.
268 citations
TL;DR: In this sample of hypertensive patients who have good access to health care and medication benefits, African Americans continued to have lower levels of blood pressure control despite considering more than 20 factors related toBlood pressure control.
253 citations
TL;DR: Anterior cingulates cortex volume is substantially smaller in association with combat-related PTSD, a finding broadly consistent with cingulate hypofunctionality in that disorder.
251 citations
TL;DR: A strong correlation was shown between the use of a cognitive aid and the correct treatment of MH and the effect was less pronounced in the more experienced CA 2 cohort, but there was still a strong correlation between performance and cognitive aid use.
Abstract: We evaluated empirically the extent to which the use of a cognitive aid during a high-fidelity simulation of a malignant hyperthermia (MH) event facilitated the correct and prompt treatment of MH. We reviewed the management of 48 simulated adult MH scenarios; 24 involving CA 1 and 24 involving CA 2
TL;DR: A nap at 3 AM improved performance and subjective report in physicians and nurses at 7:30 AM compared to a no-nap condition, and memory temporarily worsened after the nap.
TL;DR: Results indicate that HRR provides additional prognostic information in patients with HF undergoing CPX, and this variable alone may provide valuable clinical information when ventilatory expired gas analysis is not available.
TL;DR: During gait for an individual with post-stroke hemiparesis, adequate body weight support is provided via reorganized muscle coordination patterns of the paretic and non-paretic lower limbs relative to healthy slow gait.
TL;DR: In summary, IGF-1, PDGF-BB, and bFGF can be used in combination to maximize tenocyte proliferation and synergy among growth factors may provide a means to facilitate tendon engineering.
Abstract: A significant problem in flexor tendon repair is the lack of suitable graft material for reconstruction. The ex vivo production of flexor tendon graft constructs requires the expansion of primary c...
TL;DR: Both the beta4 integrin ligand-binding and cytoplasmic domains together with EGF were required for the synergistic activation of a Rac-dependent signaling pathway that was essential for keratinocyte directional migration in response to a galvanotactic stimulus.
Abstract: Endogenous DC electric fields (EF) are present during embryogenesis and are generated in vivo upon wounding, providing guidance cues for directional cell migration (galvanotaxis) required in these processes. To understand the role of beta (β)4 integrin in directional migration, the migratory paths of either primary human keratinocytes (NHK), β4 integrin-null human keratinocytes (β4−), or those in which β4 integrin was reexpressed (β4+), were tracked during exposure to EFs of physiological magnitude (100 mV/mm). Although the expression of β4 integrin had no effect on the rate of cell movement, it was essential for directional (cathodal) migration in the absence of epidermal growth factor (EGF). The addition of EGF potentiated the directional response, suggesting that at least two distinct but synergistic signaling pathways coordinate galvanotaxis. Expression of either a ligand binding–defective β4 (β4+AD) or β4 with a truncated cytoplasmic tail (β4+CT) resulted in loss of directionality in the absence of EGF, whereas inhibition of Rac1 blinded the cells to the EF even in the presence of EGF. In summary, both the β4 integrin ligand–binding and cytoplasmic domains together with EGF were required for the synergistic activation of a Rac-dependent signaling pathway that was essential for keratinocyte directional migration in response to a galvanotactic stimulus.
TL;DR: Familism was significantly correlated with lesser burden in the USA Hispanic caregiver sample, but with higher levels of depressive symptoms in the Spanish sample, denoting the importance of specific cultural contexts influencing dementia caregiving in Hispanics.
Abstract: Familism has been pointed out as a key value in Hispanic culture that may or may not be associated with caregiver distress. Although groups included in the Hispanic identity have many common features, differences between Hispanic sub-groups in the relationship of familism with burden and depressive symptoms remain unexplored. The association of familism with burden and depressive symptomatology was examined in 48 Hispanic dementia caregivers from Los Angeles (CA, USA) and 60 from Madrid (Spain) through path analyses. Burden and depressive symptomatology were positively and significantly related in both samples. Familism was significantly correlated with lesser burden in the USA Hispanic caregiver sample, but with higher levels of depressive symptoms in the Spanish sample. Significant differences between Hispanic samples were found in the relationship between familism, burden, and depression, denoting the importance of specific cultural contexts influencing dementia caregiving in Hispanics.
TL;DR: This paper proposes the concept of a "flexible regulon", which may prove to be important for pathogen evolution and the diversification of host range specificity, and defines the species- and strain-specific features of this regulon based on global gene expression profiling.
Abstract: The Bordetella master virulence regulatory system, BvgAS, controls a spectrum of gene expression states, including the virulent Bvg(+) phase, the avirulent Bvg(-) phase, and at least one Bvg-intermediate (Bvg(i)) phase. We set out to define the species- and strain-specific features of this regulon based on global gene expression profiling. Rather than functioning as a switch, Bvg controls a remarkable continuum of gene expression states, with hundreds of genes maximally expressed in intermediate phases between the Bvg(+) and Bvg(-) poles. Comparative analysis of Bvg regulation in B. pertussis and B. bronchiseptica revealed a relatively conserved Bvg(+) phase transcriptional program and identified previously uncharacterized candidate virulence factors. In contrast, control of Bvg(-)- and Bvg(i)-phase genes diverged substantially between species; regulation of metabolic, transporter, and motility loci indicated an increased capacity in B. bronchiseptica, compared to B. pertussis, for ex vivo adaptation. Strain comparisons also demonstrated variation in gene expression patterns within species. Among the genes with the greatest variability in patterns of expression, predicted promoter sequences were nearly identical. Our data suggest that the complement of transcriptional regulators is largely responsible for transcriptional diversity. In support of this hypothesis, many putative transcriptional regulators that were Bvg regulated in B. bronchiseptica were deleted, inactivated, or unregulated by BvgAS in B. pertussis. We propose the concept of a "flexible regulon." This flexible regulon may prove to be important for pathogen evolution and the diversification of host range specificity.
TL;DR: This meta-analysis of 25 studies summarizes current knowledge about the accuracy of calcaneal quantitative ultrasound for identifying adults with a dual-energy x-ray absorptiometry (DXA) T-score of 2.5 or less at the hip or spine and found no quantitative ultrasound thresholds at which sensitivity or specificity was sufficiently high to rule out or rule in DXA-determined osteoporosis.
Abstract: Studies of its test performance show that at commonly used cutoff thresholds, calcaneal quantitative ultrasound does not definitively exclude or confirm osteoporosis as diagnosed by a gold standard...
TL;DR: It is demonstrated that different levels of IHP differentially modulate hMSC chondrogenesis in the presence of TGF-beta3, suggesting that tissue engineering of articular cartilage through application or recruitment of hMSCs can be facilitated by mechanical stimulation.
Abstract: This study examined effects of varying magnitudes of intermittent hydrostatic pressure (IHP) applied for different times on chondrogenesis of adult human mesenchymal stem cells (hMSCs) in vitro. hMSCs were exposed to 0.1, 1, and 10 MPa of IHP at a frequency of 1 Hz for 4 h/day for 3, 7, and 14 days in the presence of transforming growth factor (TGF-beta3). Chondrogenesis was characterized by gene expression, macromolecule production, and extracellular matrix deposition. Exposure of hMSCs to 0.1 MPa of IHP increased SOX9 and aggrecan mRNA expression by 2.2- and 5.6-fold, respectively, whereas type II collagen mRNA expression responded maximally at 10 MPa. Production of sulfated glycosaminoglycan responded to IHP of 1 MPa and 10 MPa, whereas collagen levels increased only at 10 MPa. Morphologically, matrix condensation occurred with increased IHP, concomitant with collagen expression. This study demonstrated that different levels of IHP differentially modulate hMSC chondrogenesis in the presence of TGF-beta3. The data suggest that tissue engineering of articular cartilage through application or recruitment of hMSCs can be facilitated by mechanical stimulation.
TL;DR: The intervention reduced negative thoughts and feelings about the target transgression 2 to 3 times more effectively than the control condition, and it produced significantly greater increases in positive thoughts andfeelings toward the transgressor.
Abstract: The goal of this study was to evaluate the effects of a 6-week forgiveness intervention on three outcomes: (a) offense-specific forgiveness, (b) forgiveness-likelihood in new situations, and (c) health-related psychosocial variables, such as perceived stress and trait-anger. Participants were 259 adults who had experienced a hurtful interpersonal transgression from which they still felt negative consequences. They were randomized to a forgiveness-training program or a no-treatment control group. The intervention reduced negative thoughts and feelings about the target transgression 2 to 3 times more effectively than the control condition, and it produced significantly greater increases in positive thoughts and feelings toward the transgressor. Significant treatment effects were also found for forgiveness self-efficacy, forgiveness generalized to new situations, perceived stress, and trait-anger.
TL;DR: Results indicate that inhibition of myostatin does not protect against the onset and progression of motor neuron degenerative disease, however, the preservation of skeletal muscle during early-stage disease and improved diaphragm morphology and function maintained through late stage disease suggest that anti-myostatin therapy may promote some improved muscle function in ALS.
TL;DR: Women veteran VA patients have as heavy a burden of physical and mental illness as do men in VA, and are expected to require comparable intensity of health care services.
Abstract: BACKGROUND: Male veterans receiving Veterans Health Administration (VA) care have worse health than men in the general population. Less is known about health status in women veteran VA patients, a rapidly growing population. OBJECTIVE: To characterize health status of women (vs men) veteran VA patients across age cohorts, and assess gender differences in the effect of social support upon health status. DESIGN AND PATIENTS: Data came from the national 1999 Large Health Survey of Veteran Enrollees (response rate 63%) and included 28,048 women and 651,811 men who used VA in the prior 3 years. MEASUREMENTS: Dimensions of health status from validated Veterans Short Form-36 instrument; social support (married, living arrangement, have someone to take patient to the doctor). RESULTS: In each age stratum (18 to 44, 45 to 64, and ≥65 years), Physical Component Summary (PCS) and Mental Component Summary (MCS) scores were clinically comparable by gender, except that for those aged≥65, mean MCS was better for women than men (49.3 vs 45.9, P<.001). Patient gender had a clinically insignificant effect upon PCS and MCS after adjusting for age, race/ethnicity, and education. Women had lower levels of social support than men; in patients aged <65, being married or living with someone benefited MCS more in men than in women. CONCLUSIONS: Women veteran VA patients have as heavy a burden of physical and mental illness as do men in VA, and are expected to require comparable intensity of health care services. Their ill health occurs in the context of poor social support, and varies by age.
TL;DR: Improvements in stiff-knee gait are associated with sufficient increases in knee flexion velocity at toe-off and corresponding decreases in excessive knee extension moments during double support.
TL;DR: Statin therapy was not associated with a higher risk of severe hepatotoxicity in patients with chronic hepatitis C and appeared safe.
TL;DR: Embryonic fibroblasts from Tgfb1-/- mice were stably transfected with a reporter plasmid consisting of TGF-β responsive Smad-binding elements coupled to a secreted alkaline phosphatase reporter gene (SBE-SEAP) and MFB-F11 cells can be used to rapidly and specifically measure TGF -β with high sensitivity.
Abstract: Transforming Growth Factor-β (TGF-β) regulates key biological processes during development and in adult tissues and has been implicated in many diseases. To study the biological functions of TGF-β, sensitive, specific, and convenient bioassays are necessary. Here we describe a new cell-based bioassay that fulfills these requirements. Embryonic fibroblasts from Tgfb1-/- mice were stably transfected with a reporter plasmid consisting of TGF-β responsive Smad-binding elements coupled to a secreted alkaline phosphatase reporter gene (SBE-SEAP). Clone MFB-F11 showed more than 1000-fold induction after stimulation with 1 ng/ml TGF-β1, and detected as little as 1 pg/ml TGF-β1. MFB-F11 cells were highly induced by TGF-β1, TGF-β2 and TGF-β3, but did not show induction with related family members activin, nodal, BMP-2 and BMP-6 or with trophic factors bFGF and BDNF. MFB-F11 cells can detect and quantify TGF-β in biological samples without prior enrichment of TGF-βs, and can detect biologically activated TGF-β in a cell co-culture system. MFB-F11 cells can be used to rapidly and specifically measure TGF-β with high sensitivity.
TL;DR: The data suggest that hypoxia tends to increase blood hormone concentrations, but anorexia suppresses elements of the endocrine response, which results in the preservation of energy stores but may sacrifice the facilitation of oxygen delivery and the use of oxygen-efficient fuels.
Abstract: High-altitude anorexia leads to a hormonal response pattern modulated by both hypoxia and caloric restriction (CR). The purpose of this study was to compare altitude-induced neuroendocrine changes ...
TL;DR: It is shown that both costamerogenesis and myofibrillogenesis are initiated at sites of membrane contacts with the extracellular matrix and that their maturation is tightly coupled.
TL;DR: Cessation messages should address health risks of any smoking, ethnic differences, smoke-free messages, and situational triggers to help nondaily smokers quit with brief interventions.
TL;DR: No substantial improvement in mortality and hospital readmission during the 1990s among elderly patients hospitalized with heart failure is found, suggesting that recent innovations in heart failure management have not yet translated into better outcomes in this population.