bluuebunny/crossref_metadata_2025_split huggingface dataset:
Regulation of glial development by cystatin C
Authors: Hasegawa Akiko , Naruse Masae , Hitoshi Seiji , Iwasaki Yasuno , Takebayashi Hirohide , Ikenaka Kazuhiro 
Published: October 2006

AbstractCystatin C (CysC) is an endogenous cysteine proteases inhibitor produced by mature astrocytes in the adult brain. Previously we isolated CysC as a factor activating the glial fibrillary acidic protein (GFAP) promoter, and showed that CysC is expressed in astrocyte progenitors during development. Here we show that protease inhibitor activity increased daily in conditioned medium, and that this activity was mainly a result of CysC released from primary cultured cells. Human CysC added to the culture medium of primary brain cells increased the number of GFAP‐positive and nestin‐positive cells. Human CysC also increased the number of neurospheres formed from embryonic brain, and thus it increases the number of neural stem/precursor cells in a manner similar to glycosylated rat CysC. The addition of a neutralizing antibody, on the other hand, greatly decreased the number of GFAP and glutamate aspartate transporter (GLAST)‐positive astrocytes. This decrease was reversed by the addition of CysC but not by another cysteine protease inhibitor. Thus, the promotion of astrocyte development by CysC appears to be independent of its protease inhibitor activity. The antibody increased the number of oligodendrocytes and their precursors. Therefore, CysC modifies glial development in addition to its activity against neural stem/precursor cells.
A role for the transcriptional repressor REST in maintaining the phenotype of neurosecretory‐deficient PC12 cells
Authors: Pance Alena , Livesey Frederick J. , Jackson Antony P. 
Published: October 2006

AbstractThe rat PC12 variant cell line, A35C, lacks regulated secretory organelles due to a selective transcriptional block. Hence, A35C may provide clues about the mechanisms that underlie control of neurosecretion. We used mRNA microarray profiling to examine gene expression in A35C. Genes for regulated secretory proteins were down‐regulated, while other membrane trafficking pathways were unaffected. A subset of genes repressed in A35C contain binding sites for the neuronal transcriptional repressor, RE1‐silencing transcription factor (REST), and REST is expressed in A35C but not normal PC12 cells. Blocking the activity of REST in A35C using a dominant‐negative construct induced the reappearance of mRNAs for synaptophysin, chromogranin A, synaptotagmin IV and the β3 subunit of the voltage‐gated sodium channel (Scn3b), all of which contain RE1 sites in their genes. In the case of Scn3b, the corresponding protein was also re‐expressed. Granule and synaptic vesicle proteins were not re‐expressed at the protein level, despite reactivation of their mRNA, suggesting the existence of additional post‐transcriptional control for these proteins. Our work identifies one of the mechanisms underlying the phenotype of neurosecretory‐deficient neuroendocrine cells, and begins to define the critical components that determine a key aspect of the neuroendocrine phenotype.
Inhibition of MLK3‐MKK4/7‐JNK1/2 pathway by Akt1 in exogenous estrogen‐induced neuroprotection against transient global cerebral ischemia by a non‐genomic mechanism in male rats
Authors: Wang Ran , Zhang Quan‐Guang , Han Dong , Xu Jing , Lü Qian , Zhang Guang‐Yi 
Published: October 2006

AbstractNumerous studies have demonstrated the neuroprotective effects of estrogen in experimental cerebral ischemia. To investigate molecular mechanisms of estrogen neuroprotection in global ischemia, immunoblotting, immunohistochemistry and Nissel‐staining analysis were used. Our results showed that chronic pretreatment with β‐estradiol 3‐benzoate (E2) enhanced Akt1 activation and reduced the activation of mixed‐lineage kinase 3 (MLK3), mitogen‐activated protein kinase kinase 4/7 (MKK4/7), and c‐Jun N‐terminal kinase 1/2 (JNK1/2) in the hippocampal CA1 subfield during reperfusion after 15 min of global ischemia. In addition, E2 reduced downstream JNK nuclear and non‐nuclear components, c‐Jun and Bcl‐2 phosphorylation and Fas ligand protein expression induced by ischemia/reperfusion. Administration of phosphoinositide 3‐kinase (PI3K) inhibitor LY 294,002 prevented both activation of Akt1 and inhibition of MLK3, MKK4/7 and JNK1/2. The interaction between ERα and the p85 subunit of PI3K was also examined. E2 and antiestrogen ICI 182,780 promoted and prevented this interaction, respectively. Furthermore, ICI 182,780 blocked both the activation of Akt1 and the inhibition of MLK3, MKK4/7 and JNK1/2. Photomicrographs of cresyl violet‐stained brain sections showed that E2 reduced CA1 neuron loss after 5 days of reperfusion, which was abolished by ICI 182,780 and LY 294,002. Our data indicate that in response to estrogen, ERα interacts with PI3K to activate Akt1, which may inhibit the MLK3‐MKK4/7‐JNK1/2 pathway to protect hippocampal CA1 neurons against global cerebral ischemia in male rats.
Expression of the Wnt inhibitor Dickkopf‐1 is required for the induction of neural markers in mouse embryonic stem cells differentiating in response to retinoic acid
Authors: Verani R. , Cappuccio I. , Spinsanti P. , Gradini R. , Caruso A. , Magnotti M. C. , Motolese M. , Nicoletti F. , Melchiorri D. 
Published: October 2006

AbstractCultured mouse D3 embryonic stem (ES) cells differentiating into embryoid bodies (EBs) expressed several Wnt isoforms, nearly all isotypes of the Wnt receptor Frizzled and the Wnt/Dickkopf (Dkk) co‐receptor low‐density lipoprotein receptor‐related protein (LRP) type 5. A 4‐day treatment with retinoic acid (RA), which promoted neural differentiation of EBs, substantially increased the expression of the Wnt antagonist Dkk‐1, and induced the synthesis of the Wnt/Dkk‐1 co‐receptor LRP6. Recombinant Dkk‐1 applied to EBs behaved like RA in inducing the expression of the neural markers nestin and distal‐less homeobox gene (Dlx‐2). Recombinant Dkk‐1 was able to inhibit the Wnt pathway, as shown by a reduction in nuclear β‐catenin levels. Remarkably, the antisense‐ or small interfering RNA‐induced knockdown of Dkk‐1 largely reduced the expression of Dlx‐2, and the neuronal marker β‐III tubulin in EBs exposed to RA. These data suggest that induction of Dkk‐1 and the ensuing inhibition of the canonical Wnt pathway is required for neural differentiation of ES cells.
Sustained phosphorylation of tyrosine hydroxylase at serine 40: a novel mechanism for maintenance of catecholamine synthesis
Authors: Bobrovskaya Larisa , Gilligan Conor , Bolster Ellen K. , Flaherty Jeffrey J. , Dickson Phillip W. , Dunkley Peter R. 
Published: October 2006

AbstractTyrosine hydroxylase (TH) is the rate‐limiting enzyme in catecholamine synthesis. Its activity is known to be controlled acutely (minutes) by phosphorylation and chronically (days) by protein synthesis. Using bovine adrenal chromaffin cells we found that nicotine, acting via nicotinic receptors, sustained the phosphorylation of TH at Ser40 for up to 48 h. Nicotine also induced sustained activation of TH, which for the first 24 h was completely independent of TH protein synthesis, and the phosphorylation of TH at Ser31. Imipramine did not inhibit the acute phosphorylation of TH at Ser40 or TH activation induced by nicotine, but did inhibit the sustained responses to nicotine seen at 24 h. The protein kinase(s) responsible for TH phosphorylation at Ser40 switched from being protein kinase C (PKC) independent in the acute phase to PKC dependent in the sustained phase. Sustained phosphorylation and activation of TH were also observed with histamine and angiotensin II. Sustained phosphorylation of TH at Ser40 provides a novel mechanism for increasing TH activity and this leads to increased catecholamine synthesis. Sustained phosphorylation of TH may be a selective target for drugs or pathology in neurons that contain TH and synthesize dopamine, noradrenaline or adrenaline.
Repeated stress alters the ability of nicotine to activate the hypothalamic–pituitary–adrenal axis
Authors: Lutfy Kabirullah , Brown Maria C. , Nerio Namiko , Aimiuwu Otaren , Tran Benjamin , Anghel Adrian , Friedman Theodore C. 
Published: October 2006

AbstractAcute nicotine administration has been shown to activate the hypothalamic–pituitary–adrenal (HPA) axis and stimulate secretion of adrenocorticotrophic hormone (ACTH), corticosterone/cortisol and β‐endorphin (beta‐END) in both rodents and humans, raising the possibility that activation of the HPA axis by nicotine may mediate some of the effects of nicotine. Since stress can increase the risk of drug use and abuse, we hypothesized that repeated stress would increase the ability of nicotine to stimulate the secretion of HPA hormones. To test our hypothesis, mice were exposed to repeated stress (swimming in 15°C water for 3 min/day for 5 days) and killed 15 min after injection of saline or nicotine (0.1 mg/kg, s.c.). Repeated exposure to stress increased the ability of nicotine to stimulate plasma ACTH (p < 0.05) and beta‐END (p < 0.05), but not corticosterone secretion. In contrast, repeated exposure to stress increased the post‐saline injection levels of corticosterone (p < 0.05), but not ACTH and beta‐END. The present results suggest that chronic stress leads to an enhanced sensitivity of some components of the HPA axis to a subsequent nicotine challenge.
Alternative splicing of RGS8 gene changes the binding property to the M1 muscarinic receptor to confer receptor type‐specific Gq regulation
Authors: Itoh Masayuki , Nagatomo Katsuhiro , Kubo Yoshihiro , Saitoh Osamu 
Published: October 2006

AbstractRGS proteins constitute a large family that modulates heterotrimeric G‐protein signaling. We previously showed that RGS8 suppressed Gq signaling in a receptor type‐specific manner. To elucidate molecular mechanisms underlying receptor‐specific attenuation by RGS8, we examined whether RGS8 can interact with certain G‐protein‐coupled receptors. By pull‐down assay, we showed that RGS8 directly binds to the third intracellular (i3) loop of M1 and M3 muscarinic acetylcholine receptors (mAChRs). The binding of RGS8S, a splice variant with a different N‐terminus, was weaker. RGS8 could bind specifically to the C‐terminal part of M1i3 (containing amino acids of 304–353 of i3 of human M1‐mAChR), but RGS8S could not. Moreover, deletion of the N‐terminal 9 amino acids and substitution of both Arg‐8 and Arg‐9 of RGS8 with Ala resulted in reduced binding to M1i3. BRET experiments revealed that RGS8 actually interacts with M1‐mAChR, but RGS8S does not interact in the living cells. The RGS8 mutant, which had less binding ability to M1i3, showed a reduced inhibitory function of Gq signaling through M1‐mAChR. These results demonstrated that RGS8 can directly interact with M1‐mAChR via its N‐terminus and the i3 loop of the receptor, and this binding must play an essential role in receptor‐specific suppression by RGS8.
The heat‐shock protein 90 inhibitor 17‐allylamino‐17‐demethoxygeldanamycin suppresses glial inflammatory responses and ameliorates experimental autoimmune encephalomyelitis
Authors: Russo Cinzia Dello , Polak Paul E. , Mercado Pilar R. , Spagnolo Alessandra , Sharp Anthony , Murphy Patricia , Kamal Adeela , Burrows Francis J. , Fritz Lawrence C. , Feinstein Douglas L. 
Published: October 2006

AbstractThe heat‐shock response (HSR), a highly conserved cellular response, is characterized by rapid expression of heat‐shock proteins (HSPs), and inhibition of other synthetic activities. The HSR can attenuate inflammatory responses, via suppression of transcription factor activation. A HSR can be induced pharmacologically by HSP90 inhibitors, through activation of the transcription factor Heat Shock Factor 1 (HSF1). In the present study we characterized the effects of 17‐allylamino‐17‐demethoxygeldanamycin (17‐AAG), a less toxic derivative of the naturally occurring HSP90 inhibitor geldanamycin, on glial inflammatory responses and the development of experimental autoimmune encephalomyelitis. In primary enriched glial cultures, 17‐AAG dose dependently reduced lipopolysaccharide‐dependent expression and activity of inducible nitric oxide synthase, attenuated interleukin (IL)‐1β expression and release, increased inhibitor of κB protein levels, and induced HSP70 expression. 17‐AAG administration to mice immunized with myelin oligodendrocyte glycoprotein peptide prevented disease onset when given at an early time, and reduced clinical symptoms when given during ongoing disease. T cells from treated mice showed a reduced response to immunogen re‐stimulation, and 17‐AAG reduced CD3‐ and CD28‐dependent IL‐2 production. Together, these data suggest that HSP90 inhibitors could represent a new approach for therapeutic intervention in autoimmune diseases such as multiple sclerosis.
Improving Quality Assessment through Multilevel Modeling: The Case of Nursing Home Compare
Authors: Arling Greg , Lewis Teresa , Kane Robert L. , Mueller Christine , Flood Shannon 
Published: October 2006

Objective. To demonstrate how multilevel modeling and empirical Bayes (EB) estimates can improve Medicare's Nursing Home Compare quality measures (QMs).Data Sources/Study Setting. Secondary data from July 1 to September 30, 2004. Facility‐level QMs were estimated from minimum data set (MDS) assessments for approximately 31,000 Minnesota nursing home residents in 393 facilities.Study Design. Prevalence and incidence rates for 12 nursing facility QMs (e.g., use of physical restraints, pressure sores, and weight loss) were estimated with EB methods and risk adjustment using a hierarchical general linear model. Three sets of rates were developed: Nursing Home Compare's current method, unadjusted EB rates, and risk‐adjusted EB rates. Bayesian 90 percent credibility intervals (CIs) were constructed around EB rates, and these were used to flag facilities for potential quality of care problems.Data Collection/Extraction Methods. MDS assessments were performed by nursing facility staff, transmitted electronically to the Minnesota Department of Health, and provided to the investigators.Principal Findings. Facility rates and rankings for the 12 QMs differed substantially using the multilevel models compared with current methods. The EB estimated rates shrank considerably toward the population mean. Risk adjustment had a large impact on some QM rates and a more modest impact on others. When EB CIs were used to flag problem facilities, there was wide variation across QMs in the percentage of facilities flagged.Conclusions. Multilevel modeling should be applied to Nursing Home Compare and more widely in other health care quality assessment systems.
Organizational Culture and Physician Satisfaction with Dimensions of Group Practice
Authors: Zazzali James L. , Alexander Jeffrey A. , Shortell Stephen M. , Burns Lawton R. 
Published: October 2006

Research Objective.To assess the extent to which the organizational culture of physician group practices is associated with individual physician satisfaction with the managerial and organizational capabilities of the groups.Study Design and Methods.Physician surveys from 1997 to 1998 assessing the culture of their medical groups and their satisfaction with six aspects of group practice. Organizational culture was conceptualized using the Competing Values framework, yielding four distinct cultural types. Physician‐level data were aggregated to the group level to attain measures of organizational culture. Using hierarchical linear modeling, individual physician satisfaction with six dimensions of group practice was predicted using physician‐level variables and group‐level variables. Separate models for each of the four cultural types were estimated for each of the six satisfaction measures, yielding a total of 24 models.Sample Studied.Fifty‐two medical groups affiliated with 12 integrated health systems from across the U.S., involving 1,593 physician respondents (38.3 percent response rate). Larger medical groups and multispecialty groups were over‐represented compared with the U.S. as a whole.Principal Findings.Our models explain up to 31 percent of the variance in individual physician satisfaction with group practice, with individual organizational culture scales explaining up to 5 percent of the variance. Group‐level predictors: group (i.e., participatory) culture was positively associated with satisfaction with staff and human resources, technological sophistication, and price competition. Hierarchical (i.e., bureaucratic) culture was negatively associated with satisfaction with managerial decision making, practice level competitiveness, price competition, and financial capabilities. Rational (i.e., task‐oriented) culture was negatively associated with satisfaction with staff and human resources, and price competition. Developmental (i.e., risk‐taking) culture was not significantly associated with any of the satisfaction measures. In some of the models, being a single‐specialty group (compared with a primary care group) and a group having a higher percent of male physicians were positively associated with satisfaction with financial capabilities. Physician‐level predictors: individual physicians' ratings of organizational culture were significantly related to many of the satisfaction measures. In general, older physicians were more satisfied than younger physicians with many of the satisfaction measures. Male physicians were less satisfied with data capabilities. Primary care physicians (versus specialists) were less satisfied with price competition.Conclusion.Some dimensions of physician organizational culture are significantly associated with various aspects of individual physician satisfaction with group practice.
Do State Parity Laws Reduce the Financial Burden on Families of Children with Mental Health Care Needs?
Authors: Barry Colleen L. , Busch Susan H. 
Published: October 2006

Objective. To study the financial impact of state parity laws on families of children in need of mental health services.Data Source. Privately insured families in the 2000 State and Local Area Integrated Telephone Survey National Survey of Children with Special Health Care Needs (CSHCN) (N=38,856).Study Design. We examine whether state parity laws reduce the financial burden on families of children with mental health conditions. We use instrumental variable estimation controlling for detailed information on a child's health and functional impairment. We compare those in parity and nonparity states and those needing mental health care with other CSHCN.Principle Findings. Multivariate regression results indicate that living in a parity state significantly reduced the financial burden on families of children with mental health care needs. Specifically, the likelihood of a child's annual out‐of‐pocket (OOP) health care spending exceeding $1,000 was significantly lower among families of children needing mental health care living in parity states compared with those in nonparity states. Families with children needing mental health care in parity states were also more likely to view OOP spending as reasonable compared with those in nonparity states. Likewise, living in a parity state significantly lowered the likelihood of a family reporting that a child's health needs caused financial problems. The likelihood of reports that additional income was needed to finance a child's care was also lower among families with mentally ill children living in parity states. However, we detect no significant difference among residents of parity and nonparity states in receipt of needed mental health care.Conclusion. These results indicate that state parity laws are providing important economic benefits to families of mentally ill children undetected in prior research.
Nurse Working Conditions, Organizational Climate, and Intent to Leave in ICUs: An Instrumental Variable Approach
Authors: Stone Patricia W. , Mooney‐Kane Cathy , Larson Elaine L. , Pastor Diane K. , Zwanziger Jack , Dick Andrew W. 
Published: October 2006

Objective. To investigate causes of nurse intention to leave (ITL) while simultaneously considering organizational climate (OC) in intensive care units (ICUs) and identify policy implications.Data Sources/Study Setting. Data were obtained from multiple sources including nurse surveys, hospital administrative data, public use, and Medicare files. Survey responses were analyzed from 837 nurses employed in 39 adult ICUs from 23 hospitals located in 20 separate metropolitan statistical areas.Study Design. We used an instrumental variable technique to assess simultaneously the relationship between OC and ITL. We estimated ordinary least squares and reduced form regressions to determine the extent of simultaneity bias as well as the sensitivity of our results to the instrumental variable model specification.Principal Findings. Fifteen percent of the nurses indicated their ITL in the coming year. Based on the structural model, we found that nurses' ITL contributed little if anything directly to OC, but that OC and the tightness of the labor market had significant roles in determining ITL (p values <.05). Furthermore, OC was affected by the average regionally adjusted ICU wages, hospital profitability, teaching, and Magnet status (p values <.05).Conclusions. OC is an important determinant of ITL among ICU nurses. Because higher wages do not reduce ITL, increased pay alone without attention to OC is likely insufficient to reduce nurse turnover. Implementing interventions aimed at creating a positive OC, as found in Magnet hospitals, may be a more effective strategy.
Beyond Our Walls: Impact of Patient and Provider Coordination across the Continuum on Outcomes for Surgical Patients
Authors: Weinberg Dana Beth , Gittell Jody Hoffer , Lusenhop R. William , Kautz Cori M. , Wright John 
Published: October 2006

Objectives.To investigate patients' experience with coordination of their postsurgical care across multiple settings and the effects on key outcomes.Data Sources.Primary data collected over 18 months from 222 unilateral knee‐replacement patients at Brigham and Women's Hospital in Boston, MA.Study Design.Patients were surveyed about the coordination of their postdischarge care during the 6‐week period postdischarge when they received care from rehabilitation facilities and/or home care agencies and follow‐up care from the surgeon.Data Collection.Patients were surveyed before surgery and at 6 and 12 weeks postsurgery.Principal Findings.Patient reports highlight problems with coordination across settings and between providers and themselves. These problems, measured at 6 weeks, were associated with greater joint pain, lower functioning, and lower patient satisfaction at 6 weeks after surgery. At 12 weeks after surgery, coordination problems were associated with greater joint pain, but were not associated with functional status.Conclusion.Coordination across settings affects patients' clinical outcomes and satisfaction with their care. Although accountable for transfer to the next care setting, providers are neither accountable for nor supported to coordinate across the continuum. Addressing this system problem requires both introducing coordinating mechanisms and also supporting their use through changes in providers' incentives, resources, and time.