bluuebunny/crossref_metadata_2025_split huggingface dataset:
S100A8 and S100A9 in experimental osteoarthritis
Authors: Zreiqat Hala , Belluoccio Daniele , Smith Margaret M , Wilson Richard , Rowley Lynn A , Jones Katie , Ramaswamy Yogambha , Vogl Thomas , Roth Johannes , Bateman John F , Little Christopher B 
Published: January 2010

Abstract
Introduction
The objective was to evaluate the changes in S100A8 S100A9, and their complex (S100A8/S100A9) in cartilage during the onset of osteoarthritis (OA) as opposed to inflammatory arthritis.

Methods
S100A8 and S100A9 protein localization were determined in antigen-induced inflammatory arthritis in mice, mouse femoral head cartilage explants stimulated with interleukin-1 (IL-1), and in surgically-induced OA in mice. Microarray expression profiling of all S100 proteins in cartilage was evaluated at different times after initiation of degradation in femoral head explant cultures stimulated with IL-1 and surgically-induced OA. The effect of S100A8, S100A9 or the complex on the expression of aggrecan (Acan), collagen II (Col2a1), disintegrin and metalloproteases with thrombospondin motifs (Adamts1, Adamts 4 &Adamts 5), matrix metalloproteases (Mmp1, Mmp3, Mmp13 &Mmp14) and tissue inhibitors of metalloproteinases (Timp1, Timp2 &Timp3), by primary adult ovine articular chondrocytes was determined using real time quantitative reverse transcription polymerase chain reaction (qRT-PCR).

Results
Stimulation with IL-1 increased chondrocyte S100a8 and S100a9 mRNA and protein levels. There was increased chondrocyte mRNA expression of S100a8 and S100a9 in early but not late mouse OA. However, loss of the S100A8 staining in chondrocytes occurred as mouse OA progressed, in contrast to the positive reactivity for both S100A8 and S100A9 in chondrocytes in inflammatory arthritis in mice. Homodimeric S100A8 and S100A9, but not the heterodimeric complex, significantly upregulated chondrocyte Adamts1, Adamts4 and Adamts 5, Mmp1, Mmp3 and Mmp13 gene expression, while collagen II and aggrecan mRNAs were significantly decreased.

Conclusions
Chondrocyte derived S100A8 and S100A9 may have a sustained role in cartilage degradation in inflammatory arthritis. In contrast, while these proteins may have a role in initiating early cartilage degradation in OA by upregulating MMPs and aggrecanases, their reduced expression in late stages of OA suggests they do not have an ongoing role in cartilage degradation in this non-inflammatory arthropathy.
PDE4 inhibition drives resolution of neutrophilic inflammation by inducing apoptosis in a PKA-PI3K/Akt-dependent and NF-κB-independent manner
Authors: Sousa Lirlândia P , Lopes Fernando , Silva Douglas M , Tavares Luciana P , Vieira Angélica T , Rezende Bárbara M , Carmo Aline F , Russo Remo C , Garcia Cristiana C , Bonjardim Cláudio A , Alessandri Ana L , Rossi Adriano G , Pinho Vanessa , Teixeira Mauro M 
Published: January 2010

Abstract
PDE4 inhibition is effective at resolving neutrophilic inflammation after LPS-challenge by promoting caspase-3-dependent apoptosis of inflammatory cells in the pleural cavity.
PDE4 inhibitors are effective anti-inflammatory drugs whose effects and putative mechanisms on resolution of inflammation and neutrophil apoptosis in vivo are still unclear. Here, we examined the effects of specific PDE4 inhibition on the resolution of neutrophilic inflammation in the pleural cavity of LPS-challenged mice. LPS induced neutrophil recruitment that was increased at 4 h, peaked at 8–24 h, and declined thereafter. Such an event in the pleural cavity was preceded by increased levels of KC and MIP-2 at 1 and 2 h. Treatment with the PDE4 inhibitor rolipram, at 4 h after LPS administration, decreased the number of neutrophils and increased the percentage of apoptotic cells in the pleural cavity in a PKA-dependent manner. Conversely, delayed treatment with a CXCR2 antagonist failed to prevent neutrophil recruitment. Forskolin and db-cAMP also decreased the number of neutrophils and increased apoptosis in the pleural cavity. The proapoptotic effect of rolipram was associated with decreased levels of the prosurvival protein Mcl-1 and increased caspase-3 cleavage. The pan-caspase inhibitor zVAD-fmk prevented rolipram-induced resolution of inflammation. LPS resulted in a time-dependent activation of Akt, which was blocked by treatment with rolipram or PI3K and Akt inhibitors, and PI3K and Akt inhibitors also enhanced apoptosis and promoted neutrophil clearance. Although LPS induced NF-κB activation, which was blocked by rolipram, NF-κB inhibitors did not promote resolution of neutrophil accumulation in this model. In conclusion, our data show that PDE4 inhibition resolves neutrophilic inflammation by promoting caspase-dependent apoptosis of inflammatory cells by targeting a PKA/PI3K/Akt-dependent survival pathway.
Pivotal Advance: Nonfunctional lung effectors exhibit decreased calcium mobilization associated with reduced expression of ORAI1
Authors: Arimilli Subhashini , Sharma Sharad K , Yammani Rama , Reid Sean D , Parks Griffith D , Alexander-Miller Martha A 
Published: January 2010

Abstract
A previously unknown mechanism for the active negative regulation of function in effector T cells is described.
CD8+ T cells play a critical role in the clearance of respiratory pathogens. Thus, it is surprising that functional inactivation of lung effectors has been observed in many models of viral infection. Currently, the molecular defect responsible for the shut-off of function in these cells is unknown. In the present study, we addressed this question using a model of respiratory infection with the paramyxovirus SV5. Nonfunctional cells were found to exhibit decreases in SOCE, resulting in reduced NFAT1 activation. Notably, function could be restored by the provision of increased levels of extracellular calcium. The reduced ability to mobilize calcium was associated with reduced expression of ORAI1, the CRAC channel subunit. These findings reveal a previously unknown mechanism for the negative regulation of function in effector T cells.
TNF-α, IL-6, and IL-1 expression is inhibited by GAS6 in monocytes/macrophages
Authors: Alciato Federica , Sainaghi Pier Paolo , Sola Daniele , Castello Luigi , Avanzi Gian Carlo 
Published: January 2010

Abstract
Gas6 is able to inhibit pro-inflammatory cytokine secretion by macrophages acting on Mer receptor; the pathway involved is mediated by PI3K, Akt, GSK3β, and NFκB.
GAS6 protein has been described to be involved in immune modulation in vitro and in vivo. Some of these effects are probably mediated through the involvement of monocytes/macrophages. To understand the role of GAS6 in modulating the immune response, we evaluated the effect on cytokine secretion by monocytes/macrophages and the molecular pathways involved. GAS6 inhibits TNF-α and IL-6 secretion by LPS-stimulated U937 cells and monocytes/machrophages. We evidenced that among GAS6 receptors, only Mer (but not Axl or Tyro3) is expressed on differentiated U937 cells, and its activation is responsible for the reduction of cytokine expression. In immunoblot analysis, Mer was activated after GAS6 stimulation, giving rise to an increased phosphorylation of Akt. We also observed GSK3β phosphorylation and consequent inhibition of NF-κB nuclear translocation. Therefore, GAS6 modulates macrophage cytokine secretion, triggering an “anti-inflammatory pathway” involving PI3K/Akt/GSK3β and NF-κB.
Induction of neutrophil degranulation by S100A9 via a MAPK-dependent mechanism
Authors: Simard Jean-Christophe , Girard Denis , Tessier Philippe A 
Published: January 2010

Abstract
S100A9 induces degranulation in human neutrophils.
S100A9 is a proinflammatory protein, expressed abundantly in the cytosol of neutrophils and monocytes. High extracellular S100A9 concentrations have been correlated with chronic inflammatory diseases such as rheumatoid arthritis and Crohn's disease, as well as with phagocyte extravasation. This study tested the hypothesis that S100A9 induces degranulation in human neutrophils. S100A9 was found to up-regulate the surface expression of CD35 and CD66b, proteins contained in secretory vesicles and specific/gelatinase granules, respectively. In addition, gelatinase and albumin, stored, respectively, in specific/gelatinase granules and secretory vesicles, were detected in the supernatants of neutrophils stimulated with S100A9. In contrast, stimulation with S100A9 had no effect on CD63 expression or MPO secretion, two proteins contained in azurophilic granules. S100A9 induced the phosphorylation of the MAPKs, ERK1/2, p38, and JNK. Inhibition of p38 and JNK but not ERK1/2, with specific inhibitors (SB203580, JNKII, and PD98059, respectively), blocked neutrophil degranulation induced by S100A9. Taken together, these results support the hypothesis and clearly indicate that S100A9 induces the degranulation of secretory and specific/gelatinase granules but not of azurophilic granules in a process involving p38 and JNK and further support its classification as a DAMP.
Written Medicine Information from English-Speaking Countries—How Does It Compare?
Authors: Luk Alice , Tasker Natalie , Theo Raynor David K , Aslani Parisa 
Published: January 2010

Background: There has been an increasing drive from consumers for more information to be available about their medicines. However, the layout and presentation of such written information is variable, and the poor format and design discourages people from reading the documents. Objective: To identify, collate, and evaluate different formats of written medicine information (WMI). Methods: Three researchers evaluated 157 samples of WMI for 10 prescription and 3 over-the-counter medicines from 6 English-speaking countries compared with the United States Keystone Consensus Criterion 8 (USKCC8) and the Ten Key Principles (TKP) of Consumer Medicine Information. Readability was measured using Flesch-Kincaid Grade Level (FKGL) and Fog tests. Compliance (%) with the criteria was computed and examined using the median test. Results: Overall median compliance with USKCC8 was 70%, and 74% to TKP. New Zealand leaflets achieved the highest compliance with USKCC8 (83%, Interquartile range (IQR) 70–89%), with US leaflets the lowest (55%. IQR 45–70%). Australian and New Zealand leaflets showed the highest compliance with TKP (90%, IQR 80–100% and 87–97%, respectively), while UK leaflets demonstrated the lowest (60%, IQR 52–71%). Overall median reading grades for the leaflets were 10 (Flesch-Kincaid Grade Level) and 11 (Fog). Conclusions: Compliance with USKCC8 and TKP varied greatly between countries, with readability grades exceeding the recommended range. International examples of WMI show wide variation in compliance with guidelines on recommended format and presentation. These examples of WMI require high literacy to read. Future WMI development should use more recommended formats and increase comprehensibility.
The Role of Health Literacy and Written Medicine Information in Nonsteroidal Antiinflammatory Drug Risk Awareness
Authors: Miller Michael J , Schmitt Michael R , Allison Jeroan J , Cobaugh Daniel J , Ray Midge N , Saag Kenneth G 
Published: January 2010

Background: Despite widespread use of prescription nonsteroidal antiinflammatory drugs (NSAIDs), patients are commonly unaware of their risks. Pharmacies regularly distribute written medicine information (WMI) describing the risks and benefits of NSAID therapy at the time of dispensing. Objective: To clarify the relationship among common sociodemographic factors, education, health literacy, reading of WMI routinefy distributed at pharmacies, and NSAID risk awareness. Methods: Generalized linear latent and mixed models (GLLAMM) ordered logistic regression and confirmatory path analysis were used to evaluate multivariable relationships in a cross-sectional dataset of 382 patients in the second phase of the Alabama NSAID Patient Safety Study. Results: The majority of the analytical sample was female (72.0%) with 38.7% African American, 38.1% age 65 years or older, and 43.3% reporting at least some college education. Health literacy was positively associated with reading of WMI (p = 0.001) and NSAID risk awareness (p = 0.025), while age was negatively associated with reading WMI (p = 0.001) and NSAID risk awareness (p = 0.005). Medicaid/uninsured status was negatively associated with risk awareness (p = 0.013). Reading of WMI was not associated with NSAID risk awareness (p = 0.659). The final path model demonstrated excellent fit. Conclusions: The lack of relationship between reading of WMI and NSAID risk awareness questions the current strategy of distribution of patient-targeted print education materials at pharmacies. To maximize limited resources, future research should identify more effective strategies to deliver risk information to patients and ensure its retention, especially in high-risk groups such as the elderly, the indigent, and those with inadequate health literacy.
Diabetes: Intensive Insulin Protocol Implementation and Outcomes in the Medical and Surgical Wards at a Veterans Affairs Medical Center
Authors: Chen Helen J , Steinke Douglas T , Karounos Dennis G , Lane Matthew T , Matson Adrienne W 
Published: January 2010

Background: Hyperglycemia is an important marker for clinical outcomes and mortality in hospitalized patients. New national standards have been established emphasizing the importance of improving inpatient glycemic control in individuals with diabetes or new-onset hyperglycemia. Implementation of these new standards is complex and requires a multidisciplinary team approach. A basal-bolus insulin regimen approach has been shown to improve inpatient glycemic control. Few studies have been published regarding basal-bolus insulin protocol outcomes in the non–intensive care unit (ICU) setting. Objective: To evaluate the efficacy of a basal-bolus insulin protocol on inpatient glycemic control in a non-ICU setting, as measured by mean blood glucose and number of hypoglycemic episodes per patient admission. Methods: A retrospective, observational, single-center study was conducted to compare blood glucose control pre- (October 2006–March 2007) and postprotocol (November 2007–January 2008) implementation. Inclusion criteria consisted of patient admission to a medical or surgical ward for at least 72 hours, with a diagnosis of diabetes, or presentation with 2 blood glucose readings greater than 180 mg/dL. Patients admitted to the ICU or those not admitted to a medical or surgical ward were excluded. Results: Following protocol implementation, the mean ± SD blood glucose level increased from 174 ± 88 mg/dL to 188 ± 95 mg/dL (p < 0.001) and the hypoglycemic incidents significantly decreased, from 1.11 to 0.51 events per patient admission (p < 0.0025). Conclusions: In this pilot study, implementation of a basal-bolus insulin protocol significantly reduced hypoglycemic events; however, mean blood glucose values increased. These results suggest that a basal-bolus insulin protocol can reduce hypoglycemia; however, factors such as protocol compliance, barriers in overcoming the use of the traditional sliding scale insulin regimens, staff education, and change of work-flow habits can influence the overall efficacy and impact of a basal-bolus insulin protocol on inpatient gtycemic control.
Stability of Cyclophosphamide in Extemporaneous Oral Suspensions
Authors: Kennedy Rachel , Groepper Daniel , Tagen Michael , Christensen Robbin , Navid Fariba , Gajjar Amar , Stewart Clinton F 
Published: January 2010

Background: Cyclophosphamide, an alkylating agent, is widely used for the treatment of many adult and pediatric malignancies. The stability of cyclophosphamide in aqueous- and methylcellulose-based oral suspending vehicles is currently unknown. Objective: To develop and validate a stability-indicating high-performance liquid chromatography (HPLC) method to measure cyclophosphamide concentrations in simple syrup and Ora-Plus, and assess the 56-day chemical stability and physical appearance of cyclophosphamide in these suspensions at both room temperature (22 °C) and 4 °C. Methods: The intravenous formulation of cyclophosphamide was diluted to 20 mg/mL in NaCI 0.9%, compounded 1:1 with either suspending vehicle, and stored in the dark in 3-mL amber polypropylene oral syringes at 4 °C and 22 °C. Aliquots from each syringe were obtained on days 0.3, 7, 14, 21, 28, 35, 42, 49, and 56 and assayed using the validated stability-indicating HPLC-UV method. A C18 analytical column was used to separate cyclophosphamide from the internal standard, ifosfamide, with a mobile phase of 21% acetonitrile in 79% sodium phosphate buffer. The suspension was examined for odor change, visually examined under normal fluorescent light for color change, and examined under a light microscope for evidence of microbial growth. Results: Samples of cyclophosphamide in both simple syrup and Ora-Plus were stable when kept at 4 °C for at least 56 days. At room temperature, cyclophosphamide in simple syrup and Ora-Plus had a shell life of 8 and 3 days, respectively. No changes in color or odor or evidence of microbial growth were observed. Conclusions: Cyclophosphamide can be extemporaneously prepared in simple syrup or Ora-Plus and stored for at least 2 months under refrigeration without significant degradation.
A Practical Approach to Determine Permeability from Wireline Measurements
Authors: Al-Harbi Ahmed , Gringarten Alain , Akkurt Ridvan 
Published: January 2010

Abstract
Permeability is a crucial input to any simulation effort to forecast production. It is available from different sources: core, nuclear magnetic resonance (NMR), wireline formation tester (WFT) and drill stem test (DST). These sources are different in many aspects: the type of permeability they measure, e.g. absolute or effective, the scale of measurement in the vertical and the lateral directions and the degree of inconvenience caused by the data acquisition process in terms of operational constraints, costs, safety issues, etc.
Much effort has been invested by the industry to be able to use the most cost effective tools, NMR and WFT, for permeability measurement as substitute for the less convenient ones: core and DST. Results of these efforts are still mostly qualitative.
This work is a summary of the senior author's MSc thesis1 which reviewed the different sources of permeability and their limitations using field data from, an oil bearing, clastic reservoir that included core, NMR, WFT and DST. All these data were analyzed and interpreted for permeability evaluation. The objective of the study was to develop an approach for calibrating the static NMR permeability log with the WFT dynamic data and to compare the results with the traditional approach of calibrating with cores. Permeabilities from both approaches were upscaled for comparing with DST-derived permeabilities.
It was found that the upscaled WFT-calibrated NMR permeabilities match the DST permeabilities as satisfactorily as the upscaled core-calibrated NMR permeabilities.
Cyclin D2 Is Essential for the Compensatory β-Cell Hyperplastic Response to Insulin Resistance in Rodents
Authors: Georgia Senta , Hinault Charlotte , Kawamori Dan , Hu Jiang , Meyer John , Kanji Murtaza , Bhushan Anil , Kulkarni Rohit N. 
Published: January 2010

OBJECTIVE
A major determinant of the progression from insulin resistance to the development of overt type 2 diabetes is a failure to mount an appropriate compensatory β-cell hyperplastic response to maintain normoglycemia. We undertook the present study to directly explore the significance of the cell cycle protein cyclin D2 in the expansion of β-cell mass in two different models of insulin resistance.

RESEARCH DESIGN AND METHODS
We created compound knockouts by crossing mice deficient in cyclin D2 (D2KO) with either the insulin receptor substrate 1 knockout (IRS1KO) mice or the insulin receptor liver-specific knockout mice (LIRKO), neither of which develops overt diabetes on its own because of robust compensatory β-cell hyperplasia. We phenotyped the double knockouts and used RT-qPCR and immunohistochemistry to examine β-cell mass.

RESULTS
Both compound knockouts, D2KO/LIRKO and D2KO/IRS1KO, exhibited insulin resistance and hyperinsulinemia and an absence of compensatory β-cell hyperplasia. However, the diabetic D2KO/LIRKO group rapidly succumbed early compared with a relatively normal lifespan in the glucose-intolerant D2KO/IRS1KO mice.

CONCLUSIONS
This study provides direct genetic evidence that cyclin D2 is essential for the expansion of β-cell mass in response to a spectrum of insulin resistance and points to the cell-cycle protein as a potential therapeutic target that can be harnessed for preventing and curing type 2 diabetes.
The Protective Role of Nrf2 in Streptozotocin-Induced Diabetic Nephropathy
Authors: Jiang Tao , Huang Zheping , Lin Yifeng , Zhang Zhigang , Fang Deyu , Zhang Donna D. 
Published: January 2010

OBJECTIVEDiabetic nephropathy is one of the major causes of renal failure, which is accompanied by the production of reactive oxygen species (ROS). Nrf2 is the primary transcription factor that controls the antioxidant response essential for maintaining cellular redox homeostasis. Here, we report our findings demonstrating a protective role of Nrf2 against diabetic nephropathy.RESEARCH DESIGN AND METHODSWe explore the protective role of Nrf2 against diabetic nephropathy using human kidney biopsy tissues from diabetic nephropathy patients, a streptozotocin-induced diabetic nephropathy model in Nrf2−/− mice, and cultured human mesangial cells.RESULTSThe glomeruli of human diabetic nephropathy patients were under oxidative stress and had elevated Nrf2 levels. In the animal study, Nrf2 was demonstrated to be crucial in ameliorating streptozotocin-induced renal damage. This is evident by Nrf2−/− mice having higher ROS production and suffering from greater oxidative DNA damage and renal injury compared with Nrf2+/+ mice. Mechanistic studies in both in vivo and in vitro systems showed that the Nrf2-mediated protection against diabetic nephropathy is, at least, partially through inhibition of transforming growth factor-β1 (TGF-β1) and reduction of extracellular matrix production. In human renal mesangial cells, high glucose induced ROS production and activated expression of Nrf2 and its downstream genes. Furthermore, activation or overexpression of Nrf2 inhibited the promoter activity of TGF-β1 in a dose-dependent manner, whereas knockdown of Nrf2 by siRNA enhanced TGF-β1 transcription and fibronectin production.CONCLUSIONSThis work clearly indicates a protective role of Nrf2 in diabetic nephropathy, suggesting that dietary or therapeutic activation of Nrf2 could be used as a strategy to prevent or slow down the progression of diabetic nephropathy.