bluuebunny/crossref_metadata_2025 huggingface dataset:
Circulating endothelial progenitor cells and cellular membrane microparticles in db/db diabetic mouse: possible implications in cerebral ischemic damage
Authors: Chen Ji , Chen Shuzhen , Chen Yusen , Zhang Cheng , Wang Jinju , Zhang Wenfeng , Liu Gang , Zhao Bin , Chen Yanfang
Published: April 2011

For determining the implications of circulating endothelial progenitor cells (cEPCs) and cellular membrane microparticles (MPs) in diabetic stroke, levels of EPCs, EPC-MPs, and endothelium-derived MPs (EMPs) and their correlations with blood glucose concentration, cerebral microvascular density (cMVD), and ischemic damage were investigated in type 2 diabetic db/db and db/+ (wild-type control) mice. Therapeutic efficacy of EPC infusion (preincubated with MPs) was also explored. Ischemic stroke was induced by middle cerebral artery occlusion (MCAO) surgery. Ischemic damage and cMVD were determined using histological analyses. The levels of cEPCs and MPs were determined using flow cytometric analyses. EPC generation and functions were evaluated by in vitro cell cultures. Results showed the following. 1) In db/db mice, the basal level of cEPCs was less and cMVDs were lower, but the levels of circulating EPC-MPs and EMPs were more; 2) MCAO induced a larger infarct volume and less of an increase in cEPCs in db/db mice; 3) the level of cEPCs correlated with blood glucose concentration (negatively), cMVD (positively), and ischemic damage (negatively), but the levels of EPC-MPs and EMPs correlated inversely with those parameters; 4) EPCs were reduced and dysfunctional in db/db mice, and preincubation with db/db MPs impaired EPC functions; and 5) infusion of EPCs preincubated with db/+ MPs increased the level of cEPCs and reduced ischemic damage, and these beneficial effects were reduced or lost in EPCs preincubated with db/db MPs. These data suggest that reduced cEPCs, impaired EPC generation/function, and increased production of MPs might be the mechanisms responsible for increased ischemic damage seen in db/db mice.
Intracellular fatty acids suppress β-adrenergic induction of PKA-targeted gene expression in white adipocytes
Authors: Mottillo Emilio P. , Granneman James G.
Published: April 2011

β-Adrenergic receptor (β-AR) activation elevates cAMP levels in fat cells and triggers both metabolic and transcriptional responses; however, the potential interactions between these pathways are poorly understood. This study investigated whether lipolysis affects β-AR-mediated gene expression in adipocytes. Acute β3-adrenergic receptor (β3-AR) stimulation with CL 316,243 (CL) increased expression of PKA-targeted genes PCG-1α, UCP1, and NOR-1 in mouse white fat. Limiting lipolysis via inhibition of hormone-sensitive lipase (HSL), a direct target of PKA, sharply potentiated CL induction of PCG-1α, UCP1, and NOR-1. CL also induced greater expression of PKA-targeted genes in white fat of HSL-null mice compared with wild-type littermates, further indicating that HSL activity limits PKA-mediated gene expression. Inhibiting HSL in 3T3-L1 adipocytes also potentiated the induction of PGC-1α, UCP1, and NOR-1 by β-AR activation, as did siRNA knockdown of adipose triglyceride lipase, the rate-limiting enzyme for lipolysis. Conversely, treatments that promote intracellular fatty acid accumulation suppressed induction of PGC-1α and UCP1 through β-AR stimulation. Analysis of β-adrenergic signaling indicated that excessive intracellular fatty acid production inhibits adenylyl cyclase activity and thereby reduces PKA signaling to the nucleus. Lastly, partially limiting lipolysis by inhibition of HSL increased the induction of oxidative gene expression and mitochondrial electron transport chain activity in white adipose tissue and facilitated fat loss in mice treated for 5 days with CL. Overall, our results demonstrate that fatty acids limit the upregulation of β-AR-responsive genes in white adipocytes and suggest that limiting lipolysis may be a novel means of enhancing β-AR signaling.
Exercise increases TBC1D1 phosphorylation in human skeletal muscle
Authors: Jessen Niels , An Ding , Lihn Aina S. , Nygren Jonas , Hirshman Michael F. , Thorell Anders , Goodyear Laurie J.
Published: April 2011

Exercise and weight loss are cornerstones in the treatment and prevention of type 2 diabetes, and both interventions function to increase insulin sensitivity and glucose uptake into skeletal muscle. Studies in rodents demonstrate that the underlying mechanism for glucose uptake in muscle involves site-specific phosphorylation of the Rab-GTPase-activating proteins AS160 (TBC1D4) and TBC1D1. Multiple kinases, including Akt and AMPK, phosphorylate TBC1D1 and AS160 on distinct residues, regulating their activity and allowing for GLUT4 translocation. In contrast to extensive rodent-based studies, the regulation of AS160 and TBC1D1 in human skeletal muscle is not well understood. In this study, we determined the effects of dietary intervention and a single bout of exercise on TBC1D1 and AS160 site-specific phosphorylation in human skeletal muscle. Ten obese (BMI 33.4 ± 2.4, M-value 4.3 ± 0.5) subjects were studied at baseline and after a 2-wk dietary intervention. Muscle biopsies were obtained from the subjects in the resting (basal) state and immediately following a 30-min exercise bout (70% V̇o2 max). Muscle lysates were analyzed for AMPK activity and Akt phosphorylation and for TBC1D1 and AS160 phosphorylation on known or putative AMPK and Akt sites as follows: AS160 Ser711(AMPK), TBC1D1 Ser231(AMPK), TBC1D1 Ser660(AMPK), TBC1D1 Ser700(AMPK), and TBC1D1 Thr590(Akt). The diet intervention that consisted of a major shift in the macronutrient composition resulted in a 4.2 ± 0.4 kg weight loss ( P < 0.001) and a significant increase in insulin sensitivity ( M value 5.6 ± 0.6), but surprisingly, there was no effect on expression or phosphorylation of any of the muscle-signaling proteins. Exercise increased muscle AMPKα2 activity but did not increase Akt phosphorylation. Exercise increased phosphorylation on AS160 Ser711, TBC1D1 Ser231, and TBC1D1 Ser660but had no effect on TBC1D1 Ser700. Exercise did not increase TBC1D1 Thr590phosphorylation or TBC1D1/AS160 PAS phosphorylation, consistent with the lack of Akt activation. These data demonstrate that a single bout of exercise regulates TBC1D1 and AS160 phosphorylation on multiple sites in human skeletal muscle.
Ornithine decarboxylase is upregulated by the androgen receptor in skeletal muscle and regulates myoblast proliferation
Authors: Lee Nicole K. L. , Skinner Jarrod P. J. , Zajac Jeffrey D. , MacLean Helen E.
Published: April 2011

The aim of this study is to determine if the Odc1 gene, which encodes ornithine decarboxylase (ODC), the rate-limiting enzyme in polyamine biosynthesis, is directly regulated by the androgen receptor (AR) in skeletal muscle myoblasts and if Odc1 regulates myoblast proliferation and differentiation. We previously showed that expression of Odc1 is decreased in muscle from AR knockout male mice. In this study, we show in vivo that Odc1 expression is also decreased >60% in muscle from male muscle-specific AR knockout mice. In normal muscle homeostasis, Odc1 expression is regulated by age and sex, reflecting testosterone levels, as muscle of adult male mice expresses high levels of Odc1 compared with age-matched females and younger males. In vitro, expression of Odc1 is 10- and 1.5-fold higher in proliferating mouse C2C12and human skeletal muscle myoblasts, respectively, than in differentiated myotubes. Dihydrotestosterone increases Odc1 levels 2.7- and 1.6-fold in skeletal muscle cell myoblasts after 12 and 24 h of treatment, respectively. Inhibition of ODC activity in C2C12myoblasts by α-difluoromethylornithine decreases myoblast number by 40% and 66% following 48 and 72 h of treatment, respectively. In contrast, overexpression of Odc1 in C2C12myoblasts results in a 27% increase in cell number vs. control when cells are grown under differentiation conditions for 96 h. This prolonged proliferation is associated with delayed differentiation, with reduced expression of the differentiation markers myogenin and Myf6 in Odc1-overexpressing cells. In conclusion, androgens act via the AR to upregulate Odc1 in skeletal muscle myoblasts, and Odc1 promotes myoblast proliferation and delays differentiation.
Effects of macrophage-specific adiponectin expression on lipid metabolism in vivo
Authors: Luo Nanlan , Wang Xiangdong , Chung B. Hong , Lee Mi-Hye , Klein Richard L. , Garvey W. Timothy , Fu Yuchang
Published: April 2011

Epidemiological studies have associated low circulating levels of the adipokine adiponectin with multiple metabolic disorders, including metabolic syndrome, obesity, insulin resistance, type II diabetes, and cardiovascular disease. Recently, we reported that adiponectin selectively overexpressed in mouse macrophages can improve insulin sensitivity and protect against inflammation and atherosclerosis. To further investigate the role of adiponectin and macrophages on lipid and lipometabolism in vivo, we engineered the expression of adiponectin in mouse macrophages (Ad-TG mice) and examined effects on plasma lipoproteins and on the expression levels of genes involved in lipoprotein metabolism in tissues. Compared with the wild-type (WT) mice, Ad-TG mice exhibited significantly lower levels of plasma total cholesterol (−21%, P < 0.05) due to significantly decreased LDL (−34%, P < 0.05) and VLDL (−32%, P < 0.05) cholesterol concentrations together with a significant increase in HDL cholesterol (+41%, P < 0.05). Further studies investigating potential mechanisms responsible for the change in lipoprotein cholesterol profile revealed that adiponectin-producing macrophages altered expression of key genes in liver tissue, including apoA1, apoB, apoE, the LDL receptor, ( P < 0.05), and ATP-binding cassette G1 ( P < 0.01). In addition, Ad-TG mice also exhibited higher total and high-molecular-weight adipnection levels in plasma and increased expression of the anti-inflammatory cytokine IL-10 as well as a decrease in the proinflammatory cytokine IL-6 in adipose tissue. These results indicate that macrophages engineered to produce adiponectin can influence in vivo gene expression in adipose tissue in a manner that reduces inflammation and macrophage infiltration and in liver tissue in a manner that alters the circulating lipoprotein profile, resulting in a decrease in VLDL and LDL and an increase in HDL cholesterol. The data support further study addressing the use of genetically manipulated macrophages as a novel therapeutic approach for treatment of cardiometabolic disease.
Plasma membrane electron transport in pancreatic β-cells is mediated in part by NQO1
Authors: Gray Joshua P. , Eisen Timothy , Cline Gary W. , Smith Peter J. S. , Heart Emma
Published: April 2011

Plasma membrane electron transport (PMET), a cytosolic/plasma membrane analog of mitochondrial electron transport, is a ubiquitous system of cytosolic and plasma membrane oxidoreductases that oxidizes cytosolic NADH and NADPH and passes electrons to extracellular targets. While PMET has been shown to play an important role in a variety of cell types, no studies exist to evaluate its function in insulin-secreting cells. Here we demonstrate the presence of robust PMET activity in primary islets and clonal β-cells, as assessed by the reduction of the plasma membrane-impermeable dyes WST-1 and ferricyanide. Because the degree of metabolic function of β-cells (reflected by the level of insulin output) increases in a glucose-dependent manner between 4 and 10 mM glucose, PMET was evaluated under these conditions. PMET activity was present at 4 mM glucose and was further stimulated at 10 mM glucose. PMET activity at 10 mM glucose was inhibited by the application of the flavoprotein inhibitor diphenylene iodonium and various antioxidants. Overexpression of cytosolic NAD(P)H-quinone oxidoreductase (NQO1) increased PMET activity in the presence of 10 mM glucose while inhibition of NQO1 by its inhibitor dicoumarol abolished this activity. Mitochondrial inhibitors rotenone, antimycin A, and potassium cyanide elevated PMET activity. Regardless of glucose levels, PMET activity was greatly enhanced by the application of aminooxyacetate, an inhibitor of the malate-aspartate shuttle. We propose a model for the role of PMET as a regulator of glycolytic flux and an important component of the metabolic machinery in β-cells.
Soybean Yield along the Texas Gulf Coast during Periods of Variable Rainfall as Influenced by Soybean Cultivar and Planting Date
Authors: Grichar W. J. , Biles S. , Janak J. D. , McGuill P.
Published: April 2011

Soybeans (Glycine max) can be planted along the upper Texas Gulf Coast from mid-March through May to take advantage of early season rains and to complete harvest before hurricane season and fall rains become a problem. When average to above average rainfall was received in May through July, yields were greater with the early April to mid-April planting; however, under high rainfall conditions throughout the season, the mid-April to early May planting produced the highest yields, with yields of over 4000 kg/ha. When rainfall was below normal, late March to early April plantings produced the greatest yields. When rainfall was above average, soybeans took longer to reach harvestability regardless of cultivar or plant dates, while under drought conditions the interval between planting and harvest was reduced. However, when planting was delayed, there was a greater risk of detrimental late-season effects from southern green stink bug (Nezara viridula) or the brown stink bug (Euschistus heros).
The Effects of Erythropoietin Dose Titration during High‐Fat Diet‐Induced Obesity
Authors: Foskett Amanda , Alnaeeli Mawadda , Wang Li , Teng Ruifeng , Noguchi Constance T.
Published: April 2011

Erythropoietin (Epo) is a pleotropic cytokine with several nonhematopoietic tissue effects. High‐dose Epo treatment‐mediated effects on body weight, fat mass and glucose tolerance have recently been reported, thus extending its pleotropic effects to fat and glucose metabolism. However, the exact dose range of Epo treatment required for such effects remains unidentified to date. We investigated Epo dosage effect (up to 1000 U/kg) on hematocrit, body weight, body composition, glucose metabolism, food intake, and physical activity, during high‐fat diet‐induced obesity. We report that Epo doses (1000, 600, 300, and 150 U/kg) significantly reduced body weight gain and fat mass, while, only Epo doses of 300 U/kg and higher significantly affected glucose tolerance. None of the tested Epo doses showed any detectable effects on food intake, and only 1000 U/kg dose significantly increased physical activity, suggesting that these parameters may only be partially responsible for the metabolic effects of Epo treatment.
Rapid and Automated Analytical Methods for Redox Species Based on Potentiometric Flow Injection Analysis Using Potential Buffers
Authors: Ohura Hiroki , Imato Toshihiko
Published: April 2011

Two analytical methods, which prove the utility of a potentiometric flow injection technique for determining various redox species, based on the use of some redox potential buffers, are reviewed. The first is a potentiometric flow injection method in which a redox couple such as Fe(III)-Fe(II), Fe-Fe(CN), and bromide-bromine and a redox electrode or a combined platinum-bromide ion selective electrode are used. The analytical principle and advantages of the method are discussed, and several examples of its application are reported. Another example is a highly sensitive potentiometric flow injection method, in which a large transient potential change due to bromine or chlorine as an intermediate, generated during the reaction of the oxidative species with an Fe(III)-Fe(II) potential buffer containing bromide or chloride, is utilized. The analytical principle and details of the proposed method are described, and examples of several applications are described. The determination of trace amounts of hydrazine, based on the detection of a transient change in potential caused by the reaction with a Ce(IV)-Ce(III) potential buffer, is also described.
Delineation of Chondroid Lipoma: An Immunohistochemical and Molecular Biological Analysis
Authors: de Vreeze Ronald S. A. , van Coevorden Frits , Boerrigter Lucie , Nederlof Petra M. , Haas Rick L. , Bras Johannes , Rosenwald Andreas , Mentzel Thomas , de Jong Daphne
Published: April 2011

Aims. Chondroid lipoma (CL) is a benign tumor that mimics a variety of soft tissue tumors and is characterized by translocationt(11;16). Here, we analyze CL and its histological mimics.Methods. CL (n=4) was compared to a variety of histological mimics (n=83) for morphological aspects and immunohistochemical features including cyclinD1(CCND1). Using FISH analysis,CCND1andFUSwere investigated as potential translocation partners.Results. All CLs were strongly positive forCCND1. One of 4 myoepitheliomas,CCND1, was positive. In well-differentiated lipomatous tumors and in chondrosarcomas,CCND1was frequently expressed, but all myxoid liposarcomas were negative. FISH analysis did not give support for direct involvement ofCCND1andFUSas translocation partners.Conclusions. Chondroid lipoma is extremely rare and has several and more prevalent histological mimics. The differential diagnosis of chondroid lipomas can be unraveled using immunohistochemical and molecular support.
Chronic Inflammation and Malignancy in Ulcerative Colitis
Authors: Sunkara Sai , Swanson Garth , Forsyth Christopher B. , Keshavarzian Ali
Published: April 2011

Ulcerative colitis (UC) is a chronic inflammatory bowel disease
(IBD) associated with multiple colonic and extraintestinal
complications, the most severe being the development of colorectal
cancer (CRC). Compared to the general population, there is an
increased risk of CRC associated with UC. Although the
pathogenesis of CRC in UC is unknown, most studies have linked it
to long-standing inflammation as well as other risk factors such
as duration of disease, extent of inflammation, family history of
CRC, and coexisting conditions such as primary sclerosing
cholangitis (PSC). UC is a life-long disease for which patients
enter a vigilant screening program which includes surveillance
colonoscopy to promote early detection of CRC yet some
controversies exist regarding the cost effectiveness of
surveillance colonoscopy and improving survival. Newer modalities
such as chromoendoscopy, narrow band imaging, high definition
colonoscopy, and confocal microscopy have aided in developing a
more targeted approach for early detection of dysplasia in
surveillance colonoscopy. This review focuses on the role of
chronic colonic inflammation and dysplasia in development of
UC-associated CRC and current methods of screening, detection,
chemoprevention, and treatment of UC-associated CRC.
FOXO1 Inhibits Runx2 Transcriptional Activity and Prostate Cancer Cell Migration and Invasion
Authors: Zhang Haijun , Pan Yunqian , Zheng Li , Choe Chungyoul , Lindgren Bruce , Jensen Eric D. , Westendorf Jennifer J. , Cheng Liang , Huang Haojie
Published: April 2011

Prostate cancer patients with regional lymph node involvement at radical prostatectomy often experience disease progression to other organs, with the bone as the predominant site. The transcription factor Runx2 plays an important role in bone formation and prostate cancer cell migration, invasion, and metastasis. Here we showed that the forkhead box O (FOXO1) protein, a key downstream effector of the tumor suppressor PTEN, inhibits the transcriptional activity of Runx2 in prostate cancer cells. This inhibition was enhanced by PTEN but diminished by active Akt. FOXO1 bound to Runx2 in vitro and in vivo and suppressed Runx2's activity independent of its transcriptional function. FOXO1 inhibited Runx2-promoted migration of prostate cancer cells, whereas silencing of endogenous FOXO1 enhanced prostate cancer cell migration in a Runx2-dependent manner. Forced expression of FOXO1 also inhibited Runx2-promoted prostate cancer cell invasion. Finally, we found that expression of PTEN and the level of FOXO1 in the nucleus is inversely correlated with expression of Runx2 in a cohort of prostate cancer specimens from patients with lymph node and bone metastasis. These data reveal FOXO1 as a critical negative regulator of Runx2 in prostate cancer cells. Inactivation of FOXO1 due to frequent loss of PTEN in prostate cancer cells may leave the oncogenic activities of Runx2 unchecked, thereby driving promiscuous expression of Runx2 target genes involved in cell migration and invasion and favoring prostate cancer progression. Cancer Res; 71(9); 3257–67. ©2011 AACR.
The ABL Switch Control Inhibitor DCC-2036 Is Active against the Chronic Myeloid Leukemia Mutant BCR-ABLT315I and Exhibits a Narrow Resistance Profile
Authors: Eide Christopher A. , Adrian Lauren T. , Tyner Jeffrey W. , Mac Partlin Mary , Anderson David J. , Wise Scott C. , Smith Bryan D. , Petillo Peter A. , Flynn Daniel L. , Deininger Michael W.N. , O'Hare Thomas , Druker Brian J.
Published: April 2011

Acquired point mutations within the BCR-ABL kinase domain represent a common mechanism of resistance to ABL inhibitor therapy in patients with chronic myeloid leukemia (CML). The BCR-ABLT315I mutant is highly resistant to imatinib, nilotinib, and dasatinib, and is frequently detected in relapsed patients. This critical gap in resistance coverage drove development of DCC-2036, an ABL inhibitor that binds the switch control pocket involved in conformational regulation of the kinase domain. We evaluated the efficacy of DCC-2036 against BCR-ABLT315I and other mutants in cellular and biochemical assays and conducted cell-based mutagenesis screens. DCC-2036 inhibited autophosphorylation of ABL and ABLT315I enzymes, and this activity was consistent with selective efficacy against Ba/F3 cells expressing BCR-ABL (IC50: 19 nmol/L), BCR-ABLT315I (IC50: 63 nmol/L), and most kinase domain mutants. Ex vivo exposure of CML cells from patients harboring BCR-ABL or BCR-ABLT315I to DCC-2036 revealed marked inhibition of colony formation and reduced phosphorylation of the direct BCR-ABL target CrkL. Cell-based mutagenesis screens identified a resistance profile for DCC-2036 centered around select P-loop mutations (G250E, Q252H, Y253H, E255K/V), although a concentration of 750 nmol/L DCC-2036 suppressed the emergence of all resistant clones. A decreased concentration of DCC-2036 (160 nmol/L) in dual combination with either nilotinib or dasatinib achieved the same zero outgrowth result. Further screens for resistance due to BCR-ABL compound mutations (two mutations in the same clone) identified BCR-ABLE255V / T315I as the most resistant mutant. Taken together, these findings support continued evaluation of DCC-2036 as an important new agent for treatment-refractory CML. Cancer Res; 71(9); 3189–95. ©2011 AACR.
mRNA and microRNA Expression Profiles in Circulating Tumor Cells and Primary Tumors of Metastatic Breast Cancer Patients
Authors: Sieuwerts Anieta M. , Mostert Bianca , Bolt-de Vries Joan , Peeters Dieter , de Jongh Felix E. , Stouthard Jacqueline M.L. , Dirix Luc Y. , van Dam Peter A. , Van Galen Anne , de Weerd Vanja , Kraan Jaco , van der Spoel Petra , Ramírez-Moreno Raquel , van Deurzen Carolien H.M. , Smid Marcel , Yu Jack X. , Jiang John , Wang Yixin , Gratama Jan W. , Sleijfer Stefan , Foekens John A. , Martens John W.M.
Published: April 2011

Purpose: Molecular characterization of circulating tumor cells (CTC) holds great promise. Unfortunately, routinely isolated CTC fractions currently still contain contaminating leukocytes, which makes CTC-specific molecular characterization extremely challenging. In this study, we determined mRNA and microRNA (miRNA) expression of potentially CTC-specific genes that are considered to be clinically relevant in breast cancer.

Experimental Design: CTCs were isolated with the epithelial cell adhesion molecule–based CellSearch Profile Kit. Selected genes were measured by real-time reverse transcriptase PCR in CTCs of 50 metastatic breast cancer patients collected before starting first-line systemic therapy in blood from 53 healthy blood donors (HBD) and in primary tumors of 8 of the patients. The molecular profiles were associated with CTC counts and clinical parameters and compared with the profiles generated from the corresponding primary tumors.

Results: We identified 55 mRNAs and 10 miRNAs more abundantly expressed in samples from 32 patients with at least 5 CTCs in 7.5 mL of blood compared with samples from 9 patients without detectable CTCs and HBDs. Clustering analysis resulted in 4 different patient clusters characterized by 5 distinct gene clusters. Twice the number of patients from cluster 2 to 4 had developed both visceral and nonvisceral metastases. Comparing transcript levels in CTCs with those measured in corresponding primary tumors showed clinically relevant discrepancies in estrogen receptor and HER2 levels.

Conclusions: Our study shows that molecular profiling of low numbers of CTCs in a high background of leukocytes is feasible and shows promise for further studies on the clinical relevance of molecular characterization of CTCs. Clin Cancer Res; 17(11); 3600–18. ©2011 AACR.
Caffeine Decreases Phospho-Chk1 (Ser317) and Increases Mitotic Cells with Cyclin B1 and Caspase 3 in Tumors from UVB-Treated Mice
Authors: Lu Yao-Ping , Lou You-Rong , Peng Qing-Yun , Nghiem Paul , Conney Allan H.
Published: April 2011

Oral administration of caffeine to mice inhibits UVB-induced carcinogenesis, and these results are paralleled by epidemiology studies indicating that caffeinated coffee and tea intake (but not decaffeinated beverage intake) is associated with decreased incidence of nonmelanoma skin cancer. Topical applications of caffeine to the skin of SKH-1 mice that had previously been treated with UVB inhibited subsequent skin tumor development and stimulated apoptosis in tumors but not in nontumor areas of the epidermis. This study sought to determine the basis of these differential effects on tumor versus nontumor sites that can be induced by caffeine, long after all UVB treatment has ceased. The activation status of the ATR/Chk1 pathway in UVB-induced tumors and uninvolved skin was determined by quantitating phospho-Chk1 (Ser317) and induction of lethal mitosis in vivo in the presence and absence of topical caffeine treatment. In the absence of caffeine, we found that UVB-induced tumors often had islands of phospho-Chk1 (Ser317) staining cells that were not present in nontumor areas of the epidermis. Treatment of mice with topical caffeine significantly diminished phospho-Chk1 (Ser317) staining and increased the number of mitotic cells that expressed cyclin B1 and caspase 3 in tumors, consistent with caffeine-induced lethal mitosis selectively in tumors. We hypothesize that compared with adjacent uninvolved skin, UVB-induced skin tumors have elevated activation of, and dependence on, the ATR/Chk1 pathway long after UVB exposure has ceased and that caffeine can induce apoptosis selectively in tumors by inhibiting this pathway and promoting lethal mitosis. Cancer Prev Res; 4(7); 1118–25. ©2011 AACR.
A Combination Procedure with Double C-Shaped Skin Incision and Dual-Floor Burr Hole Method to Prevent Skin Erosion on the Scalp and Reduce Postoperative Skin Complications in Deep Brain Stimulation
Authors: Park Young Seok , Kang Jeong-Han , Kim Hae Yu , Kang Dong Wan , Chang Won Seok , Kim Joo Pyung , Chang Jin Woo
Published: April 2011

Background: The purpose of this study was to introduce a combination procedure with double C-shaped skin incision and an adjusted dual-floor burr hole to prevent skin complications on the scalp with deep brain stimulation (DBS) surgery. Methods: Between March 2000 and March 2010, 504 DBS electrodes were implanted in 268 patients. We included both bilateral and unilateral DBS surgery cases for Parkinson’s disease, tremor, pain, obsessive-compulsive disorder and intractable seizure accompanied with cranial and IPG insertion procedure, but excluded motor cortex stimulation, and spinal cord stimulation. We used a straight skin incision in 118 patients, double C-shaped skin incision only in 113 patients since March 2006, and combined a double C-shaped skin incision and dual-floor burr hole in 37 patients since August 2009. We compared scalp wound complications and the height subscale of the Vancouver Scar Scale between previous straight or C-shaped skin incision and the combination procedure. Results: We had eight scalp erosions associated with infection (3.0%) and six disconnection (2.2%) cases among 268 patients. Before the use of the double C- skin incision or adjusted dual-floor burr hole technique, we had 5 (4.2%) scalp erosion cases among 118 patients. With the introduction of the C-shaped incision, only 3 patients (2.7%) developed scalp erosion. However, no patient among 37 patients developed scalp erosion after using both double C-shaped skin incision and dual-floor burr hole technique. Scalp bump measured by the height subscale of the Vancouver Scar Scale was more cosmetic in the combination procedure. Conclusion: The combination procedure prevents skin complications associated with DBS surgery, with tensile strength, less impaired vascular supply and better cosmetic outcome. This promising approach prevents unwanted skin complications associated with DBS surgery and improves patient satisfaction.
Delayed Parkinson’s Disease Diagnosis among African-Americans: The Role of Reporting of Disability
Authors: Dahodwala Nabila , Karlawish Jason , Siderowf Andrew , Duda John E. , Mandell David S.
Published: April 2011

Background/Aims: Racial differences in the observed prevalence of Parkinson’s disease (PD) may be due to delayed diagnosis among African-Americans. We sought to compare the stage at which African-American and white PD patients present for healthcare, and determine whether perception of disability accounts for racial differences. Methods: Using records of veterans with newly diagnosed PD at the Philadelphia Veterans Affairs Medical Center, we calculated differences in reporting of symptoms as the difference in z-scores on the Unified Parkinson Disease Rating Scale part 2 (disability) and part 3 (motor impairment). Ordinal logistic regression was used to determine predictors of stage at diagnosis. Results: African-American (n = 16) and white (n = 58) veterans with a mean age of 70.1 years were identified. African-Americans presented at a later PD stage than whites (median Hoehn + Yahr stage 2.5 vs. 2.0, p = 0.02) and were more likely to under-report disability relative to motor impairment (81 vs. 40%, p < 0.01). Multivariate analysis showed that under-reporting of disability accounted for much of the effect of race on stage of diagnosis. Conclusions: Under-reporting of disability among African-Americans may account for later stages of PD diagnosis than whites. This study begins to explain the mechanisms underlying observed racial disparities in PD.
Spoken Language Skills and Educational Placement in Finnish Children with Cochlear Implants
Authors: Lonka Eila , Hasan Marja , Komulainen Erkki
Published: April 2011

Objective: This study reports the demographics, and the auditory and spoken language development as well as educational settings, for a total of 164 Finnish children with cochlear implants. Methods: Two questionnaires were employed: the first, concerning day care and educational placement, was filled in by professionals for rehabilitation guidance, and the second, evaluating language development (categories of auditory performance, spoken language skills, and main mode of communication), by speech and language therapists in audiology departments. Results: Nearly half of the children were enrolled in normal kindergartens and 43% of school-aged children in mainstream schools. Categories of auditory performance were observed to grow in relation to age at cochlear implantation (p < 0.001) as well as in relation to proportional hearing age (p < 0.001). The composite scores for language development moved to more diversified ones in relation to increasing age at cochlear implantation and proportional hearing age (p < 0.001). Children without additional disorders outperformed those with additional disorders. Conclusion: The results indicate that the most favorable age for cochlear implantation could be earlier than 2. Compared to other children, spoken language evaluation scores of those with additional disabilities were significantly lower; however, these children showed gradual improvements in their auditory perception and language scores.
Evaluation of a modified thromboelastography assay for the screening of von Willebrand disease
Authors: Topf Hans-Georg , Weiss Dominik , Lischetzki Grischa , Strasser Erwin , Rascher Wolfgang , Rauh Manfred
Published: April 2011

Thromboelastography (TEG) has been shown to be a valuable point-of-care device for the rapid diagnosis of various bleeding disorders. However, TEG has thus far not been used for the screening for von Willebrand disease (VWD). We evaluated the performance of a modified TEG assay for the laboratory screening of VWD. Three hundred twenty-eight patients (148 male, 180 female, median age 8.4 years, range 0.1 – 72.7 years) were included in the study. The diagnosis and classification of patients was based on personal and familial case history, von Willebrand factor antigen, ristocetin cofactor levels, collagen binding assay, factor VIII coagulant activity and multimer analysis. The ratio of clot strength after preincubation with ristocetin, and without ristocetin, represents the component of clot strength that is formed by cross-linked fibrin fibres and is dependent on the agglutinated platelet fraction. The decrease of the maximum amplitude is a function of the ristocetin concentration and provides a diagnostic parameter able to differentiate between healthy individuals and patients having VWD. Based on a preliminary cut-off value of 25% for the area under the curve (AUC) ratio, the sensitivity varied from 53% to 100% for the different VWD patient groups. The test is suitable for use as a screening test using whole blood and has the additional benefit of being suitable as a point of care test. It appears also useful for monitoring responses to desmopressin (DDAVP) and infusion therapy.
Recent Changes in Practice of Elective Percutaneous Coronary Intervention for Stable Angina
Authors: Ahmed Bina , Dauerman Harold L. , Piper Winthrop D. , Robb John F. , Verlee M. Peter , Ryan Thomas J. , Goldberg David , Boss Richard A. , Phillips William J. , Fedele Frank , Butzel David , Malenka David J.
Published: April 2011

Background—

The COURAGE (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation) trial was designed to compare optimal medical therapy alone versus optimal medical therapy and percutaneous coronary intervention (PCI) for treatment of patients with stable coronary artery disease and showed equal efficacy for optimal medical therapy with or without PCI. The impact of results from the COURAGE trial on clinical practice is unknown.

Methods and Results—

We analyzed 26 388 consecutive patients from the Northern New England Cardiovascular Disease PCI Registry who underwent PCI between January 2006 and June 2009. We identified a COURAGE-like patient group as patients who were undergoing (1) an elective procedure; (2) for an indication of stable angina; and (3) on the day of admission (ie, the date of admission was the same as the procedure date). All other PCI patients were placed in an “other indications” cohort. We compared temporal trends in overall volume in PCI for stable angina and for other indications, comparing quarterly time periods before and after release of COURAGE in March 2007. Over the study period, there was a statistically significant decrease in total PCI volume from 2064 in Quarter 1 2006 (before COURAGE) to 1708 in Quarter 3 2007 (after COURAGE) (
P
<0.01). These trends were sustained through June 2009, with an approximate 16% peak relative reduction in all PCI compared with before COURAGE. As a percentage of all PCI, stable angina reached a high of 20.9% before COURAGE and began to decrease immediately after publication of COURAGE in Quarter 2 2007 to 16.1% (
P
<0.01). Among patients undergoing PCI for stable angina, there was a significant 26% peak decrease in post-COURAGE PCI volumes compared with pre-COURAGE Quarter 1 2006 (
P
trend, 0.01), which was maintained through the end of the study period.

Conclusions—

Publication of results from the COURAGE trial was temporally associated with a significant and sustained decline in the use of PCI to treat patients with stable angina. The long-term impact of this change in practice on patient outcomes remains to be determined.
Prompt Repeat Testing After Out-of-Range INR Values
Authors: Rose Adam J. , Hylek Elaine M. , Berlowitz Dan R. , Ash Arlene S. , Reisman Joel I. , Ozonoff Al
Published: April 2011

Background—

Improved control of oral anticoagulation reduces adverse events. A program of quality measurement is needed for oral anticoagulation. The interval until the next test after an out-of-range International Normalized Ratio (INR) value (the “follow-up interval”) could serve as a process of care measure.

Methods and Results—

We studied 104 451 patients cared for by 100 anticoagulation clinics in the Veterans Health Administration (VA). For each site, we computed the average follow-up interval after low (≤1.5) or high (≥4.0) INR. Our outcome was each site's average anticoagulation control, measured by percent time in therapeutic range (TTR); 59 837 patients (57%) contributed to the low INR analysis, 37 697 (36%) contributed to the high INR analysis, and all patients contributed to the dependent variable (mean site TTR). After a low INR, site mean follow-up interval ranged from 10 to 24 days. Longer follow-up intervals were associated with worse site-level control (1.04% lower for each additional day,
P
<0.001). After a high INR, site mean follow-up interval ranged from 6 to 18 days, with longer follow-up intervals associated with worse site-level control (1.12% lower for each additional day,
P
<0.001). These relationships were somewhat attenuated but still highly statistically significant when the proportion of INR values in-range was used as the dependent variable rather than TTR.

Conclusions—

Prompt repeat testing after out-of-range INR values is associated with better anticoagulation control at the site level and could be an important part of a quality improvement effort for oral anticoagulation.
Environmental Sustainability and Behavioral Science
Authors: Osbaldiston Richard , Schott John Paul
Published: April 2011

To provide practitioners with useful information about how to promote proenvironmental behavior (PEB), a meta-analysis was performed on 87 published reports containing 253 experimental treatments that measured an observed, not self-reported, behavioral outcome. Most studies combined multiple treatments, and this confounding precluded definitive conclusions about which individual treatments are most effective. Treatments that included cognitive dissonance, goal setting, social modeling, and prompts provided the overall largest effect sizes (Hedge’s g > 0.60). Further analyses indicated that different treatments have been more effective for certain behaviors. Although average effect sizes are based on small numbers of studies, effective combinations of treatments and behaviors are making it easy to recycle, setting goals for conserving gasoline, and modeling home energy conservation. The results also reveal several gaps in the literature that should guide further research, including both treatments and PEB that have not been tested.
“I Once Was Lost, but Now Am Found”
Authors: Jett Christopher Charlie
Published: April 2011

The lack of mathematics academic achievement and persistence in African American male students is well documented in the K-12 education research literature. Moreover, it has been documented that this trend of mathematics underachievement continues in higher education for some African American men. In this article, the author refutes the myth that African American male students are doomed to mathematics failure by drawing on research literature that highlights the strengths of African American male learners and by documenting the “voice” of an African American male doctoral student.Coupling critical race theory with case study research, the author chronicles the schooling, mathematics, and racial experiences of an African American male student. The author concludes the article by challenging those invested in the mathematics education of African American male students to work to ensure that African American male students are provided access to the mathematics pipeline.
Relationship between Saturated Fatty Acids and Periodontal Disease
Authors: Iwasaki M. , Manz M.C. , Moynihan P. , Yoshihara A. , Muramatsu K. , Watanabe R. , Miyazaki H.
Published: April 2011

Saturated fatty acids (SFAs) produce an inflammatory response. Hyperinflammation is now recognized as one of the key underlying etiologic factors in periodontal disease. The longitudinal relationship between dietary SFAs and periodontal disease in 264 Japanese individuals, aged 75 years, for whom data were available for the years 2003-2004, was investigated. SFA intake was assessed with a brief self-administered diet history questionnaire. Participants were classified by quartiles of SFA intake. Full-mouth periodontal status, measured as the clinical attachment level (CAL), was recorded at baseline and follow-up examinations. The number of teeth with a loss of CAL ≥ 3 mm at any site over a year was calculated as ‘periodontal disease events’. Poisson regression analysis was conducted, with dietary SFAs as the primary predictor of interest, to estimate their influence on periodontal disease events. High dietary SFA intake was significantly associated with a greater number of periodontal disease events among non-smokers. The multivariate adjusted relative risk (95% confidence intervals) in the 1st, 2nd, 3rd, and 4th quartiles of dietary SFAs was 1.00, 1.19 (0.72-1.97), 1.55 (0.95-2.52), and 1.92 (1.19-3.11), respectively. These findings suggest an independent association of dietary SFA intake to the progression of periodontal disease in older Japanese non-smokers.Abbreviations: saturated fatty acid (SFA); clinical attachment level (CAL); Toll-like receptor (TLR); lipopolysaccharide (LPS); brief self-administered diet history questionnaire (BDHQ); decayed, missing, and filled teeth (DMFT); clinical attachment level (CAL); body mass index (BMI); relative risk (RR); confidence intervals (CI); nuclear factor-kappa B (NF-κB).
Keeping up Appearances: Aesthetic Labour and Discrimination Law
Authors: Waring Peter
Published: April 2011

There is growing evidence of corporate demand for employees who have aesthetic qualities that can be deployed in marketing and branding strategies. This article critically examines these efforts to prefer those who ‘look good’ or possess the ‘right look’. It is argued that these strategies, designed to profit from the aesthetic qualities of employees, are exclusory and may cause harm in the same way as other discriminatory practices. Yet Australian jurisdictions, with the exception of the state of Victoria, have not addressed this challenge. An analysis of the facts and reasoning in the matter of Hopper & Ors v. Virgin Blue Airlines Pty Ltd [2004, 2005 & 2006] reveals a need for discrimination law to provide adequate remedies for those discriminated against for not possessing the ‘right look’.
Evaluation of a home-based physiotherapy programme for those with moderate to severe multiple sclerosis: a randomized controlled pilot study
Authors: Miller L , Paul L , Mattison P , McFadyen A
Published: April 2011

Objective: To investigate the effect of an eight-week home-based physiotherapy programme in reducing physical impairment, disability and psychological distress for people with moderate to severe multiple sclerosis (MS).

Design: Pilot randomized controlled trial.

Setting: Community; subjects’ homes.

Subjects: Thirty people moderately to severely affected by MS (Extended Disability Status Score, EDSS, 6.5–8) were randomized to an intervention or control group.

Intervention: The intervention group received twice weekly, home-based physiotherapy for eight weeks and the control group received usual care.

Main measures: The following outcome measures were recorded at baseline, post-intervention (Week 8) and at follow-up (Week 16). Primary outcome measure; Multiple Sclerosis Impact Scale (MSIS29) and secondary outcome measures assessed physical impairment, MS symptoms, quality of life, mood, and disability.

Results: Although the Group * Time interaction failed to reach statistical significance with MSIS29 (p = 0.925), MS – related symptom checklist (MS-RS) (p = 0.627) and for lower limb strength, right knee extension (p = 0.375) and right knee flexion (p = 0.794), there is more evidence of altered levels in the treatment group than in the control group.

Conclusion: A minimum of 58 subjects per group are required to achieve a power of 80% at the 5% level of significance based on the MSIS29. A larger scale study is required.
Facilitation of motor and balance recovery by thermal intervention for the paretic lower limb of acute stroke: a single-blind randomized clinical trial
Authors: Chen Jia-Ching , Lin Chun-Hsiang , Wei Yu-Chun , Hsiao Jung , Liang Chung-Chao
Published: April 2011

Objective: To evaluate the effectiveness of thermal stimulation accompanied by either active or passive movement added to standard rehabilitation in facilitating motor and balance function of the paretic leg of acute stroke.

Design: Pilot, observer-blinded, randomized clinical trial.

Setting: Department of rehabilitation medicine in a general hospital.

Subjects: Thirty-six patients were enrolled within four weeks of the onset of a stroke causing moderate to severe leg paresis (Brunnstrom stage ≤III).

Interventions: Patients were randomly assigned to thermal (standard rehabilitation plus approximately 30–40 minutes of thermal stimulation therapy daily for six weeks) and control (standard rehabilitation only) groups.

Main measures: Fugl–Meyer lower extremity score, Medical Research Council scale for lower extremity, Modified Motor Assessment Scale, Postural Assessment Scale for Stroke Patients Trunk Control, Berg Balance Scale, Functional Ambulation Classification and Modified Ashworth Scale.

Results: Patients in the thermal group experienced significantly better median scores for Fugl–Meyer lower extremity (14.0; interquartile range, 10.5–15.5), Medical Research Council scale for lower extremity (6.0; 4.0–7.0), Modified Motor Assessment Scale (16.0; 12.5–18.5), Berg Balance Scale (28.0; 20.5–33.5), and Functional Ambulation Classification (2.0; 2.0–2.0) (all P < 0.05). The thermal group also had more independent walkers (15/17; 88.2%) than the control group (9/16; 56.3%) after six weeks ( P = 0.06). No adverse effect occurred.

Conclusions: Thermal stimulation accompanied by either manual facilitation or encouragement for active participation of the paretic lower limb may be an effective promising supplementary treatment for the early-phase rehabilitation of moderate to severe stroke that warrants additional study.