bluuebunny/crossref_metadata_2025 huggingface dataset:
Chronic Inhibition of Dipeptidyl Peptidase-4 With a Sitagliptin Analog Preserves Pancreatic β-Cell Mass and Function in a Rodent Model of Type 2 Diabetes
Authors: Mu James , Woods John , Zhou Yun-Ping , Roy Ranabir Sinha , Li Zhihua , Zycband Emanuel , Feng Yue , Zhu Lan , Li Cai , Howard Andrew D. , Moller David. E. , Thornberry Nancy A. , Zhang Bei B.
Published: May 2006

Inhibitors of dipeptidyl peptidase-4 (DPP-4), a key regulator of the actions of incretin hormones, exert antihyperglycemic effects in type 2 diabetic patients. A major unanswered question concerns the potential ability of DPP-4 inhibition to have beneficial disease-modifying effects, specifically to attenuate loss of pancreatic β-cell mass and function. Here, we investigated the effects of a potent and selective DPP-4 inhibitor, an analog of sitagliptin (des-fluoro-sitagliptin), on glycemic control and pancreatic β-cell mass and function in a mouse model with defects in insulin sensitivity and secretion, namely high-fat diet (HFD) streptozotocin (STZ)-induced diabetic mice. Significant and dose-dependent correction of postprandial and fasting hyperglycemia, HbA1c, and plasma triglyceride and free fatty acid levels were observed in HFD/STZ mice following 2–3 months of chronic therapy. Treatment with des-fluoro-sitagliptin dose dependently increased the number of insulin-positive β-cells in islets, leading to the normalization of β-cell mass and β-cell–to–α-cell ratio. In addition, treatment of mice with des-fluoro-sitagliptin, but not glipizide, significantly increased islet insulin content and improved glucose-stimulated insulin secretion in isolated islets. These findings suggest that DPP-4 inhibitors may offer long-lasting efficacy in the treatment of type 2 diabetes by modifying the courses of the disease.
Apoptosis Signal-Regulating Kinase 1 Mediates Cellular Senescence Induced by High Glucose in Endothelial Cells
Authors: Yokoi Toyohiko , Fukuo Keisuke , Yasuda Osamu , Hotta Mizuo , Miyazaki Junichi , Takemura Yukihiro , Kawamoto Hidenobu , Ichijo Hidenori , Ogihara Toshio
Published: May 2006

Vascular ageing is accelerated in patients with diabetes. However, the underlying mechanism remains unclear. Here, we show that high glucose induces activation of apoptosis signal-regulating kinase 1 (ASK1), an apoptosis-inducing signal that mediates endothelial cell senescence induced by hyperglycemia. High glucose induced a time-dependent increase in the levels of ASK1 expression and its activity in human umbilical vein endothelial cells (HUVECs). Incubation of endothelial cells with high glucose increased the proportion of cells expressing senescence-associated β-galactosidase (SA-β-gal) activity. However, transfection with an adenoviral construct including a dominant negative form of ASK1 gene significantly inhibited SA-β-gal activity induced by high glucose. In addition, infection with an adenoviral construct expressing the constitutively active ASK1 gene directly induced an increase in the levels of SA-β-gal activity. Activation of the ASK1 signal also enhanced plasminogen activator inhibitor-1 (PAI-1) expression in HUVECs. Induction of senescent endothelial cells in aortas and elevation of plasma PAI-1 levels were observed in streptozotocin (STZ) diabetic mice, whereas these changes induced by STZ were attenuated in ASK1-knockout mice. Our results suggest that hyperglycemia accelerates endothelial cell senescence and upregulation of PAI-1 expression through activation of the ASK1 signal. Thus, ASK1 may be a new therapeutic target to prevent vascular ageing and thrombosis in diabetic patients.
Reversal of Type 1 Diabetes by Engineering a Glucose Sensor in Skeletal Muscle
Authors: Mas Alex , Montané Joel , Anguela Xavier M. , Muñoz Sergio , Douar Anne M. , Riu Efren , Otaegui Pedro , Bosch Fatima
Published: May 2006

Type 1 diabetic patients develop severe secondary complications because insulin treatment does not guarantee normoglycemia. Thus, efficient regulation of glucose homeostasis is a major challenge in diabetes therapy. Skeletal muscle is the most important tissue for glucose disposal after a meal. However, the lack of insulin during diabetes impairs glucose uptake. To increase glucose removal from blood, skeletal muscle of transgenic mice was engineered both to produce basal levels of insulin and to express the liver enzyme glucokinase. After streptozotozin (STZ) administration of double-transgenic mice, a synergic action in skeletal muscle between the insulin produced and the increased glucose phosphorylation by glucokinase was established, preventing hyperglycemia and metabolic alterations. These findings suggested that insulin and glucokinase might be expressed in skeletal muscle, using adeno-associated viral 1 (AAV1) vectors as a new gene therapy approach for diabetes. AAV1-Ins+GK–treated diabetic mice restored and maintained normoglycemia in fed and fasted conditions for >4 months after STZ administration. Furthermore, these mice showed normalization of metabolic parameters, glucose tolerance, and food and fluid intake. Therefore, the joint action of basal insulin production and glucokinase activity may generate a “glucose sensor” in skeletal muscle that allows proper regulation of glycemia in diabetic animals and thus prevents secondary complications.
Mutations at the Same Residue (R50) of Kir6.2 (KCNJ11) That Cause Neonatal Diabetes Produce Different Functional Effects
Authors: Shimomura Kenju , Girard Christophe A.J. , Proks Peter , Nazim Joanna , Lippiat Jonathan D. , Cerutti Franco , Lorini Renata , Ellard Sian , Hattersley Andrew T. , Barbetti Fabrizio , Ashcroft Frances M.
Published: May 2006

Heterozygous mutations in the human Kir6.2 gene (KCNJ11), the pore-forming subunit of the ATP-sensitive K+ channel (KATP channel), are a common cause of neonatal diabetes. We identified a novel KCNJ11 mutation, R50Q, that causes permanent neonatal diabetes (PNDM) without neurological problems. We investigated the functional effects this mutation and another at the same residue (R50P) that led to PNDM in association with developmental delay. Wild-type or mutant Kir6.2/SUR1 channels were examined by heterologous expression in Xenopus oocytes. Both mutations increased resting whole-cell currents through homomeric and heterozygous KATP channels by reducing channel inhibition by ATP, an effect that was larger in the presence of Mg2+. However the magnitude of the reduction in ATP sensitivity (and the increase in the whole-cell current) was substantially larger for the R50P mutation. This is consistent with the more severe phenotype. Single–R50P channel kinetics (in the absence of ATP) did not differ from wild type, indicating that the mutation primarily affects ATP binding and/or transduction. This supports the idea that R50 lies in the ATP-binding site of Kir6.2. The sulfonylurea tolbutamide blocked heterozygous R50Q (89%) and R50P (84%) channels only slightly less than wild-type channels (98%), suggesting that sulfonylurea therapy may be of benefit for patients with either mutation.
Significant Linkage of BMI to Chromosome 10p in the U.K. Population and Evaluation of GAD2 as a Positional Candidate
Authors: Groves Christopher J. , Zeggini Eleftheria , Walker Mark , Hitman Graham A. , Levy Jonathan C. , O’Rahilly Stephen , Hattersley Andrew T. , McCarthy Mark I. , Wiltshire Steven
Published: May 2006

Obesity is a major health problem, and many family-based studies have suggested that it has a strong genetic basis. We performed a genome-wide quantitative trait linkage scan for loci influencing BMI in 573 pedigrees from the U.K. We identified genome-wide significant linkage (logarithm of odds = 3.74, between D10S208 and D10S196, genome-wide P = 0.0186) on chromosome 10p. The size of our study population and the statistical significance of our findings provide substantial contributions to the body of evidence for a locus on chromosome 10p. We examined eight single nucleotide polymorphisms (SNPs) in GAD2, which maps to this linkage region, tagging the majority of variation in the gene, and observed marginally significant (0.01 < P < 0.05) associations between four common variants and BMI. However, these SNPs did not account for our evidence of linkage to BMI, and they did not replicate (in direction of effect) the previous associations. We therefore conclude that these SNPs are not the etiological variants underlying this locus. We cannot rule out the possibility that other untagged variations in GAD2 may, in part, be involved, but it is most likely that alternative gene(s) within the broad gene-rich region of linkage on 10p are responsible for variation in body mass and susceptibility to obesity.
Peroxisome Proliferator–Activated Receptor α Improves Pancreatic Adaptation to Insulin Resistance in Obese Mice and Reduces Lipotoxicity in Human Islets
Authors: Lalloyer Fanny , Vandewalle Brigitte , Percevault Frédéric , Torpier Gérard , Kerr-Conte Julie , Oosterveer Maaike , Paumelle Réjane , Fruchart Jean-Charles , Kuipers Folkert , Pattou François , Fiévet Catherine , Staels Bart
Published: May 2006

Peroxisome proliferator–activated receptor (PPAR) α is a transcription factor controlling lipid and glucose homeostasis. PPARα-deficient (−/−) mice are protected from high-fat diet–induced insulin resistance. However, the impact of PPARα in the pathophysiological setting of obesity-related insulin resistance is unknown. Therefore, PPARα−/− mice in an obese (ob/ob) background were generated. PPARα deficiency did not influence the growth curves of the obese mice but surprisingly resulted in a severe, age-dependent hyperglycemia. PPARα deficiency did not aggravate peripheral insulin resistance. By contrast, PPARα−/− ob/ob mice developed pancreatic β-cell dysfunction characterized by reduced mean islet area and decreased insulin secretion in response to glucose in vitro and in vivo. In primary human pancreatic islets, PPARα agonist treatment prevented fatty acid–induced impairment of glucose-stimulated insulin secretion, apoptosis, and triglyceride accumulation. These results indicate that PPARα improves the adaptative response of the pancreatic β-cell to pathological conditions. PPARα could thus represent a promising target in the prevention of type 2 diabetes.
The Role of Phosphoinositide 3-Kinase/Akt Signaling in Low-Dose Mercury–Induced Mouse Pancreatic β-Cell Dysfunction In Vitro and In Vivo
Authors: Chen Ya Wen , Huang Chun Fa , Tsai Keh Sung , Yang Rong Sen , Yen Cheng Chieh , Yang Ching Yao , Lin-Shiau Shoei Yn , Liu Shing Hwa
Published: May 2006

The relationship between oxidation stress and phosphoinositide 3-kinase (PI3K) signaling in pancreatic β-cell dysfunction remains unclear. Mercury is a well-known toxic metal that induces oxidative stress. Submicromolar-concentration HgCl2 or methylmercury triggered reactive oxygen species (ROS) production and decreased insulin secretion in β-cell–derived HIT-T15 cells and isolated mouse islets. Mercury increased PI3K activity and its downstream effector Akt phosphorylation. Antioxidant N-acetyl-l-cysteine (NAC) prevented mercury-induced insulin secretion inhibition and Akt phosphorylation but not increased PI3K activity. Inhibition of PI3K/Akt activity with PI3K inhibitor or by expressing the dominant-negative p85 or Akt prevented mercury-induced insulin secretion inhibition but not ROS production. These results indicate that both PI3K and ROS independently regulated Akt signaling–related, mercury-induced insulin secretion inhibition. We next observed that 2- or 4-week oral exposure to low-dose mercury to mice significantly caused the decrease in plasma insulin and displayed the elevation of blood glucose and plasma lipid peroxidation and glucose intolerance. Akt phosphorylation was shown in islets isolated from mercury-exposed mice. NAC effectively antagonized mercury-induced responses. Mercury-induced in vivo effects and increased blood mercury were reversed after mercury exposure was terminated. These results demonstrate that low-dose mercury–induced oxidative stress and PI3K activation cause Akt signaling–related pancreatic β-cell dysfunction.
Poly(ADP-Ribose) Polymerase Inhibition Alleviates Experimental Diabetic Sensory Neuropathy
Authors: Ilnytska Olga , Lyzogubov Valeriy V. , Stevens Martin J. , Drel Viktor R. , Mashtalir Nazar , Pacher Pal , Yorek Mark A. , Obrosova Irina G.
Published: May 2006

Poly(ADP-ribose) polymerase (PARP) activation is emerging as a fundamental mechanism in the pathogenesis of diabetes complications including diabetic neuropathy. This study evaluated the role of PARP in diabetic sensory neuropathy. The experiments were performed in control and streptozotocin-induced diabetic rats treated with or without the PARP inhibitor 1,5-isoquinolinediol (ISO; 3 mg · kg−1 · day−1 i.p.) for 2 weeks after 2 weeks without treatment. Diabetic rats developed thermal hyperalgesia (assessed by paw-withdrawal and tail-flick tests), mechanical hyperalgesia (von Frey anesthesiometer/rigid filaments and Randall-Sellito tests), tactile allodynia (flexible von Frey filaments), and increased flinching behavior in phases 1 and 2 of the 2% formalin pain test. They also had clearly manifest increase in nitrotyrosine and poly(ADP-ribose) immunoreactivities in the sciatic nerve and increased superoxide formation (hydroxyethidine method) and nitrotyrosine immunoreactivity in vasa nervorum. ISO treatment alleviated abnormal sensory responses, including thermal and mechanical hyperalgesia and tactile allodynia as well as exaggerated formalin flinching behavior in diabetic rats, without affecting the aforementioned variables in the control group. Poly(ADP-ribose) and, to a lesser extent, nitrotyrosine abundance in sciatic nerve, as well as superoxide and nitrotyrosine formation in vasa nervorum, were markedly reduced by ISO therapy. Apoptosis in dorsal root ganglion neurons (transferase-mediated dUTP nick-end labeling assay) was not detected in any of the groups. In conclusion, PARP activation contributes to early diabetic sensory neuropathy by mechanisms that may include oxidative stress but not neuronal apoptosis.
The Variable Number of Tandem Repeats Upstream of the Insulin Gene Is a Susceptibility Locus for Latent Autoimmune Diabetes in Adults
Authors: Desai Minal , Zeggini Eleftheria , Horton Virginia A. , Owen Katharine R. , Hattersley Andrew T. , Levy Jonathan C. , Hitman Graham A. , Walker Mark , Holman Rury R. , McCarthy Mark I. , Clark Anne
Published: May 2006

The etiopathological relationship between latent autoimmune diabetes in adults (LADA) and classical type 1 (insulin dependent) diabetes remains unclear. Variation at the insulin gene variable number of tandem repeats (VNTR) minisatellite influences susceptibility to type 1 diabetes, but studies in LADA have been small and inconsistent. We examined the role of insulin gene variation (using flanking variants as surrogates for VNTR subtypes) in the largest case-control study of LADA to date (400 case and 332 control subjects). Highly significant associations were identified with disease, with dominant protective effects of the T allele at −23HphI (odds ratio [OR] 0.42 [95% CI 0.31–0.58], P = 2.4 × 10−8), A allele at +1,404Fnu4HI (0.50 [0.36–0.70], P = 3.2 × 10−5), and C allele at +3,580MspI (0.55 [0.35–0.85], P = 0.0046). As with type 1 diabetes, the −23HphI variant (a surrogate for the subdivision of VNTR into class I and III alleles) most clearly defined susceptibility in LADA. However, there was no association with age at diagnosis or requirement for insulin therapy 6 years postdiagnosis. This study establishes that variation within the insulin gene region does influence susceptibility to LADA, with the direction and magnitude of effect indistinguishable from that previously reported for type 1 diabetes. In conclusion, differences in VNTR-encoded susceptibility do not explain the differences in clinical presentation that distinguish classical type 1 diabetes and LADA.
Increased Infiltration of Macrophages in Omental Adipose Tissue Is Associated With Marked Hepatic Lesions in Morbid Human Obesity
Authors: Cancello Raffaella , Tordjman Joan , Poitou Christine , Guilhem Gaël , Bouillot Jean Luc , Hugol Danielle , Coussieu Christiane , Basdevant Arnaud , Hen Avner Bar , Bedossa Pierre , Guerre-Millo Michèle , Clément Karine
Published: May 2006

In human obesity, white adipose tissue (WAT) is enriched in macrophages. How macrophage infiltration in WAT contributes to the complications of obesity is unknown. This study tested the hypothesis that recruitment of macrophages in omental WAT is associated with hepatic damage in obese patients. Paired biopsies of subcutaneous and omental WAT and a liver biopsy were collected during gastric surgery in 46 obese women and 9 obese men (BMI 47.9 ± 0.93 kg/m2). The number of HAM56+ macrophages in WAT was quantified microscopically, and correlations with clinical and biological parameters and histological liver pathology were investigated. There were twice as many macrophages in omental as in subcutaneous WAT (P < 0.0001). After adjustment for age, omental WAT macrophage infiltration was correlated to fasting glucose and insulin, quantitative insulin sensitivity check index, triglycerides, aspartate aminotransferase (AST), and γ-glutamyltranspeptidase. We propose an easy equation to estimate the amount of macrophages in omental WAT. Increased macrophage accumulation specifically in omental WAT was associated with hepatic fibroinflammatory lesions (P = 0.01). The best predictive model for the severity of hepatic damage includes adiponectinemia, AST, and omental WAT macrophages. These data suggest that the presence of macrophages in omental WAT participates in the cellular mechanisms favoring hepatic fibroinflammatory lesions in obese patients.
Effect of Calorie Restriction With or Without Exercise on Insulin Sensitivity, β-Cell Function, Fat Cell Size, and Ectopic Lipid in Overweight Subjects
Authors: Larson-Meyer D. Enette , Heilbronn Leonie K. , Redman Leanne M. , Newcomer Bradley R. , Frisard Madlyn I. , Anton Steve , Smith Steven R. , Alfonso Anthony , Ravussin Eric ,   the Pennington CALERIE Team
Published: May 2006

OBJECTIVE—The purpose of this article was to determine the relationships among total body fat, visceral adipose tissue (VAT), fat cell size (FCS), ectopic fat deposition in liver (intrahepatic lipid [IHL]) and muscle (intramyocellular lipid [IMCL]), and insulin sensitivity index (Si) in healthy overweight, glucose-tolerant subjects and the effects of calorie restriction by diet alone or in conjunction with exercise on these variables.

RESEARCH DESIGN AND METHODS—Forty-eight overweight volunteers were randomly assigned to four groups: control (100% of energy requirements), 25% calorie restriction (CR), 12.5% calorie restriction +12.5% energy expenditure through structured exercise (CREX), or 15% weight loss by a low-calorie diet followed by weight maintenance for 6 months (LCD). Weight, percent body fat, VAT, IMCL, IHL, FCS, and Si were assessed at baseline and month 6.

RESULTS—At baseline, FCS was related to VAT and IHL (P < 0.05) but not to IMCL. FCS was also the strongest determinant of Si (P < 0.01). Weight loss at month 6 was 1 ± 1% (control, mean ± SE), 10 ± 1% (CR), 10 ± 1% (CREX), and 14 ± 1% (LCD). VAT, FCS, percent body fat, and IHL were reduced in the three intervention groups (P < 0.01), but IMCL was unchanged. Si was increased at month 6 (P = 0.05) in the CREX (37 ± 18%) and LCD (70 ± 34%) groups (P < 0.05) and tended to increase in the CR group (40 ± 20%, P = 0.08). Together the improvements in Si were related to loss in weight, fat mass, and VAT, but not IHL, IMCL, or FCS.

CONCLUSIONS—Large adipocytes lead to lipid deposition in visceral and hepatic tissues, promoting insulin resistance. Calorie restriction by diet alone or with exercise reverses this trend.
Fibrillar Growth in Polyaniline
Authors: Zhang X. , Kolla H. S. , Wang X. , Raja K. , Manohar S. K.
Published: May 2006

Large, colorless aggregates are observed during the induction period of a chemical oxidative polymerization of aniline in dilute aqueous acids using an ammonium peroxydisulfate oxidant. Observed for the first time by static and dynamic light‐scattering (LS) measurements, these aggregates are believed to be anilinium–peroxydisulfate ion clusters whose shape (spherical or rodlike) plays an important role in the overall morphology of the emeraldine salt formed (granular or fibrillar). The role of these aggregates in influencing the morphology of polyaniline is further evaluated under a variety of reaction conditions, for example, varying ionic strength, concentration, temperature, nitrogen substitution, and so forth.
Three‐Dimensional SiCN Ceramic Microstructures via Nano‐Stereolithography of Inorganic Polymer Photoresists
Authors: Pham T. A. , Kim D.‐P. , Lim T.‐W. , Park S.‐H. , Yang D.‐Y. , Lee K.‐S.
Published: May 2006

We report a newly synthesized inorganic polymer photoresist with a high ceramic yield by the functionalization of polyvinylsilazane (KiON VL20) with 2‐isocyanatoethyl methacrylate via linkage or insertion reaction routes. The chemistry of the synthesis and the pyrolytic conversion as well as the mechanical evaluation were investigated by using various analytical instruments. We show for the first time that this photosensitive resin is a novel precursor for the fabrication of complex 3D SiCN ceramic microstructures with a 210 nm resolution via a two‐photon absorbed crosslinking process and subsequent pyrolysis at 600 °C under a nitrogen atmosphere. Moreover, the dimensional deformation during pyrolysis was significantly reduced by adding silica nanoparticles as a filler. In particular, the ceramic microstructures containing 40 wt % silica nanoparticles exhibited a relatively isotropic shrinkage owing to its sliding free from the substrate during pyrolysis.
Controlling the Edge Length of Gold Nanoprisms via a Seed‐Mediated Approach
Authors: Millstone J. E. , Métraux G. S. , Mirkin C. A.
Published: May 2006

A straightforward method is investigated for controlling and reinitiating the growth of single‐crystalline Au nanoprisms. This work is based on seeding methodology, and depends on the slow reduction of metal ions onto the surface of a growing nanoprism. In this manner, we can tailor the edge length of Au nanoprisms between 100 and 300 nm without changing their thickness or crystallinity. Each nanoprism size has been characterized by UV‐vis‐NIR (NIR: near‐IR) spectroscopy, transmission electron microscopy (TEM) techniques, and statistical analysis. Based on this work and existing silver halide crystal‐growth theories, a preliminary mechanism is proposed which comments on the interplay between crystal growth and surface chemistry that ultimately dictates the morphology of the resulting nanostructure.
Thermodynamics of wax precipitation under the influence of magnetic fields
Authors: Cañas‐Marin W. A. , Ortiz‐Arango J. D. , Guerrero‐Aconcha U. E. , Lira‐Galeana C.
Published: May 2006

A thermodynamic framework is developed for calculating wax precipitation in multicomponent (nonferromagnetic) hydrocarbon mixtures under the influence of a static magnetic field. A mathematical expression was derived for calculating the compositional derivatives of the magnetic susceptibilities using an equation of state. These susceptibilities are required for calculating magneto‐chemical fugacities. The model was used to predict the effect of a static magnetic field on crystallization temperature and amount of precipitated wax for three normal‐paraffin mixtures and one synthetic gas‐condensate. Calculated results indicate that static magnetic fields increase the probability of formation of paraffin crystals, in accordance to the experimental evidence. © 2006 American Institute of Chemical Engineers AIChE J, 2006
Potassium channels Kv1.3 and Kv1.5 are expressed on blood‐derived dendritic cells in the central nervous system
Authors: Mullen Katherine M. , Rozycka Monika , Rus Horea , Hu Lina , Cudrici Cornelia , Zafranskaia Ekaterina , Pennington Michael W. , Johns David C. , Judge Susan I. V. , Calabresi Peter A.
Published: May 2006

Objective

Potassium (K+) channels on immune cells have gained attention recently as promising targets of therapy for immune‐mediated neurological diseases such as multiple sclerosis (MS). We examined K+ channels on dendritic cells (DCs), which infiltrate the brain in MS and may impact disease course.

Methods

We identified K+ channels on blood‐derived DCs by whole‐cell patch‐clamp analysis, confirmed by immunofluorescent staining. We also stained K+ channels in brain sections from MS patients and control subjects. To test functionality, we blocked Kv1.3 and Kv1.5 in stimulated DCs with pharmacological blockers or with an inducible dominant‐negative Kv1.x adenovirus construct and analyzed changes in costimulatory molecule upregulation.

Results

Electrophysiological analysis of DCs showed an inward‐rectifying K+ current early after stimulation, replaced by a mix of voltage‐gated Kv1.3‐ and Kv1.5‐like channels at later stages of maturation. Kv1.3 and Kv1.5 were also highly expressed on DCs infiltrating MS brain tissue. Of note, we found that CD83, CD80, CD86, CD40, and interleukin‐12 upregulation were significantly impaired on Kv1.3 and Kv1.5 blockade.

Interpretation

These data support a functional role of Kv1.5 and Kv1.3 on activated human DCs and further define the mechanisms by which K+ channel blockade may act to suppress immune‐mediated neurological diseases. Ann Neurol 2006
Dynamic shear stimulation of bovine cartilage biosynthesis of proteoglycan 4
Authors: Nugent Gayle E. , Aneloski Nicole M. , Schmidt Tannin A. , Schumacher Barbara L. , Voegtline Michael S. , Sah Robert L.
Published: May 2006

Objective

The boundary lubrication function of articular cartilage is mediated in part by proteoglycan 4 (PRG4) molecules at the articular surface and in synovial fluid. The objective of this study was to determine the effects of dynamic shear stimulation on PRG4 biosynthesis by bovine cartilage explants.

Methods

Cartilage disks with intact articular surfaces were harvested from immature bovines. Some disks were subjected to 24 hours (day 1) of loading, consisting of a step load of 20% static compression either alone or with superimposed dynamic shear (3% amplitude and 0.1 Hz), while other disks were cultured free‐swelling as controls. After the 24‐hour loading period, disks were terminated or were further incubated for up to 72 hours (days 2–4) in free‐swelling culture to assess chondrocyte responses to, and following, unloading. PRG4 products secreted into culture medium were quantified by enzyme‐linked immunosorbent assay and characterized by Western blotting. Chondrocytes expressing PRG4 were localized by immunohistochemistry, and depth‐associated variations in chondrocyte PRG4 expression were quantified by image analysis.

Results

Dynamic shear stimulation increased PRG4 secretion to 3–4 times that of unloaded controls and statically compressed samples. Sheared cartilage secreted more PRG4 of 345 kd relative to smaller molecular weight species, as compared with unloaded controls. Immunohistochemistry revealed that shear stimulation also increased the total number of cells expressing PRG4 by inducing expression by cells at a depth of 200–400 μm.

Conclusion

The paradigm that certain mechanical stimuli up‐regulate biosynthesis in cartilage appears operative not only for load‐bearing matrix constituents, but also for PRG4 molecules that mediate lubrication.
Unusually high frequency of autoantibodies to PL‐7 associated with milder muscle disease in Japanese patients with polymyositis/dermatomyositis
Authors: Yamasaki Yoshioki , Yamada Hidehiro , Nozaki Toshiko , Akaogi Jun , Nichols Cody , Lyons Robert , Chin Loy Anthony , Chan Edward K. L. , Reeves Westley H. , Satoh Minoru
Published: May 2006

Objective

Autoantibodies to aminoacyl transfer RNA synthetases, such as histidyl (Jo‐1), threonyl (PL‐7), alanyl (PL‐12), glycyl (EJ), and isoleucyl (OJ), are closely associated with a subset of patients with polymyositis/dermatomyositis (PM/DM) complicated by interstitial lung disease (ILD). Anti–Jo‐1 is by far the most common, found in 15–25% of patients with PM/DM, whereas the other types are found in only ∼3% of these patients. In this study, the clinical associations of these autoantibodies in Japanese patients with PM/DM were investigated.

Methods

The diagnoses of PM/DM and amyopathic DM (ADM) were based on the Bohan and Peter criteria and Sontheimer's definition, respectively. Sera from 36 Japanese patients with PM/DM (13 with PM, 20 with DM, 3 with ADM) were screened by immunoprecipitation and by enzyme‐linked immunosorbent assay (for Jo‐1). Clinical and laboratory data were collected.

Results

The frequencies of autoantibodies to Jo‐1 (22%) and to EJ, OJ, and PL‐12 (3–6%) were similar to those found in previous studies, including studies of Japanese subjects. However, anti–PL‐7 was found in 17% of patients, in contrast to a frequency of 1–4% in previous studies (P < 0.02–0.0002). The 6 anti–PL‐7–positive patients were not related, and no skewing in year or month of disease development, place of residence or work, or occupation was found. All patients had ILD, consistent with the clinical features of antisynthetase‐positive patients. The patients with anti–PL‐7 had lower serum muscle enzyme levels and milder muscle weakness (P < 0.05) compared with anti–Jo‐1–positive patients.

Conclusion

Anti–PL‐7 was found at an unusually high frequency in this group of Japanese patients with myositis. Although anti–PL‐7, similar to anti–Jo‐1, is associated with PM/DM with ILD, muscle involvement in the patients with anti–PL‐7 appeared to be milder than that in the anti–Jo‐1 subset.
Endothelial dysfunction in rat adjuvant‐induced arthritis: Vascular superoxide production by NAD(P)H oxidase and uncoupled endothelial nitric oxide synthase
Authors: Haruna Yoshisuke , Morita Yoshitaka , Komai Norio , Yada Toyotaka , Sakuta Takeo , Tomita Naruya , Fox David A. , Kashihara Naoki
Published: May 2006

Objective

To investigate endothelial function and levels of vascular oxidative stress in rat adjuvant‐induced arthritis (AIA), in view of mounting evidence for an association between rheumatoid arthritis (RA) and accelerated vascular disease.

Methods

Thoracic aortic rings were prepared from AIA and control rats. After preconstriction by norepinephrine, the vasodilatory response to acetylcholine was determined. The amounts of 4‐hydroxy‐2‐nonenal (HNE) and nitrotyrosine in AIA rat aortas were measured by Western blotting. Homogenates of the aortas were incubated with various substrates for superoxide‐producing enzymes, and superoxide production was assessed by fluorogenic oxidation of dihydroethidium to ethidium. Expression of endothelial nitric oxide synthase (eNOS) in aortas was examined by real‐time reverse transcriptase–polymerase chain reaction and Western blotting. Serum levels of tetrahydrobiopterin (BH4), a critical eNOS cofactor, were determined by high‐performance liquid chromatography.

Results

Endothelium‐dependent relaxation of the aortic ring was significantly depressed in AIA rats compared with control rats. The amounts of HNE and nitrotyrosine were increased in AIA rat aortas, indicating overproduction of reactive oxygen species. Incubation of AIA rat aorta homogenates with NADH or L‐arginine, a substrate of eNOS, resulted in a significant increase in superoxide production. Endothelial NOS was highly expressed in AIA rat aortas. Serum levels of BH4 were significantly lower in AIA. Treatment of AIA with BH4 reversed the endothelial dysfunction, suggesting that its deficiency may contribute to the uncoupling of eNOS.

Conclusion

Vascular dysfunction in RA can be partially modeled in animals. NAD(P)H oxidase and uncoupled eNOS are responsible for the increase in vascular oxidative stress, which is likely to be involved in the endothelial dysfunction in AIA.
Lack of association between chondrocalcinosis and increased risk of cartilage loss in knees with osteoarthritis: Results of two prospective longitudinal magnetic resonance imaging studies
Authors: Neogi T. , Nevitt M. , Niu J. , LaValley M. P. , Hunter D. J. , Terkeltaub R. , Carbone L. , Chen H. , Harris T. , Kwoh K. , Guermazi A. , Felson D. T.
Published: May 2006

Objective

To evaluate the relationship between chondrocalcinosis and the progression of knee osteoarthritis (OA) using longitudinal magnetic resonance imaging (MRI) assessments.

Methods

Longitudinal knee MRIs were obtained in the Boston OA Knee Study (BOKS) and in the Health, Aging and Body Composition (Health ABC) Study. Chondrocalcinosis was determined as present or absent on baseline knee radiographs. Cartilage morphology was graded on paired longitudinal MRIs using the Whole‐Organ Magnetic Resonance Imaging Score in 5 cartilage subregions of each of the medial and lateral tibiofemoral joints. Cartilage loss in a subregion was defined as an increase in the cartilage score of ≥1 (0–4 scale). The risk for change in the number of subregions with cartilage loss was assessed using Poisson regression, with generalized estimating equations to account for correlations. Analyses were adjusted for age, sex, body mass index, baseline cartilage score, and presence of damaged menisci.

Results

In BOKS, 23 of the 265 included knees (9%) had chondrocalcinosis. In Health ABC, 373 knees were included, of which 69 knees (18.5%) had chondrocalcinosis. In BOKS, knees with chondrocalcinosis had a lower risk of cartilage loss compared with knees without chondrocalcinosis (adjusted risk ratio [RR] 0.4, 95% confidence interval [95% CI] 0.2–0.7) (P = 0.002), and there was no difference in risk in Health ABC (adjusted RR 0.9, 95% CI 0.6–1.5) (P = 0.7). Stratification by intact versus damaged menisci produced similar results within each cohort.

Conclusion

In knees with OA, the presence of chondrocalcinosis was not associated with increased cartilage loss. These findings do not support the hypothesis that chondrocalcinosis worsens OA progression.
E‐mail interviewing in qualitative research: A methodological discussion
Authors: Meho Lokman I.
Published: May 2006

This article summarizes findings from studies that employed electronic mail (e‐mail) for conducting in‐depth interviewing. It discusses the benefits of, and the challenges associated with, using e‐mail interviewing in qualitative research. The article concludes that while a mixed mode interviewing strategy should be considered when possible, e‐mail interviewing can be in many cases a viable alternative to face‐to‐face and telephone interviewing. A list of recommendations for carrying out effective e‐mail interviews is presented.
Evaluation of the effects of various culture conditions on Cr(VI) reduction by Shewanella oneidensis MR‐1 in a novel high‐throughput mini‐bioreactor
Authors: Tang Yinjie J. , Laidlaw David , Gani Kishen , Keasling Jay D.
Published: May 2006

The growth and Cr(VI) reduction by Shewanella oneidensis MR‐1 was examined using a mini‐bioreactor system that independently monitors and controls pH, dissolved oxygen (DO), and temperature for each of its 24, 10‐mL reactors. Independent monitoring and control of each reactor in the cassette allows the exploration of a matrix of environmental conditions known to influence S. oneidensis chromium reduction. S. oneidensis MR‐1 grew in minimal medium without amino acid or vitamin supplementation under aerobic conditions but required serine and glycine supplementation under anaerobic conditions. Growth was inhibited by DO concentrations >80%. Lactate transformation to acetate was enhanced by low concentration of DO during the logarithmic growth phase. Between 11 and 35°C, the growth rate obeyed the Arrhenius reaction rate‐temperature relationship, with a maximum growth rate occurring at 35°C. S. oneidensis MR‐1 was able to grow over a wide range of pH (6–9). At neutral pH and temperatures ranging from 30 to 35°C, S. oneidensis MR‐1 reduced 100 µM Cr(VI) to Cr(III) within 20 min in the exponential growth phase, and the growth rate was not affected by the addition of chromate; it reduced chromate even faster at temperatures between 35 and 39°C. At low temperatures (<25°C), acidic (pH < 6.5), or alkaline (pH > 8.5) conditions, 100 µM Cr(VI) strongly inhibited growth and chromate reduction. The mini‐bioreactor system enabled the rapid determination of these parameters reproducibly and easily by performing very few experiments. Besides its use for examining parameters of interest to environmental remediation, the device will also allow one to quickly assess parameters for optimal production of recombinant proteins or secondary metabolites. © 2006 Wiley Periodicals, Inc.
Aspen SP1, an exceptional thermal, protease and detergent‐resistant self‐assembled nano‐particle
Authors: Wang Wang‐Xia , Dgany Or , Wolf Sharon Grayer , Levy Ilan , Algom Rachel , Pouny Yehonathan , Wolf Amnon , Marton Ira , Altman Arie , Shoseyov Oded
Published: May 2006

Stable protein 1 (SP1) is a homo‐oligomeric protein isolated from aspen (Populus tremula aspen) plants which forms a ring‐shape dodecameric particle with a central cavity. The oligomeric form of SP1 is an exceptionally stable structure that is resistant to proteases (e.g., trypsin, V8, and proteinase K), high temperatures, organic solvents, and high levels of ionic detergent. Analytical ultra‐centrifugation, chemical cross‐linking, matrix‐assisted laser‐desorption time‐of‐flight mass spectrometry (MALDI‐TOF‐MS), and transmission electron microscopy were used to further characterize the SP1 dodecamer. Introduction of a single cysteine at the N‐terminus of SP1 enabled the formation of disulfide bridges within the SP1 dodecamer, concurrent with increased melting point. A six‐histidine tag was introduced at the N‐terminus of SP1 to generate 6HSP1, and the ΔNSP1 mutant was generated by a deletion of amino acids 2–6 at the N‐terminus. Both 6HSP1 and ΔNSP1 maintained their ability to assemble a stable dodecamer. Remarkably, these SP1 homo‐dodecamers were able to re‐assemble into stable hetero‐dodecamers following co‐electro‐elution from SDS–PAGE. The exceptional stability of the SP1‐nano ring and its ability to self‐assemble hetero‐complexes paves the way to further research in utilizing this unique protein in nano‐biotechnology. © 2006 Wiley Periodicals, Inc.
Conjugated Polyelectrolytes—Conformation‐Sensitive Optical Probes for Staining and Characterization of Amyloid Deposits
Authors: Nilsson K. Peter R. , Hammarström Per , Ahlgren Fredrik , Herland Anna , Schnell Edrun A. , Lindgren Mikael , Westermark Gunilla T. , Inganäs Olle
Published: May 2006

Specific markers for diseases associated with protein aggregate depositions are of great interest. Here we report the use of conjugated polyelectrolytes as conformation‐sensitive optical probes for histological labeling of amyloid deposits in ex vivo tissue samples—amyloid light chains in primary systemic amyloidosis, islet amyloid polypeptide in human pancreas, and Aβ amyloid in Alzheimer's disease. Under suitable conditions, these probes bind specifically to amyloid deposits, and this is seen as an orange‐red emission from the polyelectrolyte. Furthermore, the probes emit light of different colors when bound to different amyloid deposits or other intracellular structures. This phenomenon is most probably due to differences in the protein conformation in these structures. Hence, different protein conformations will generate geometric alterations of the bound polyelectrolyte backbone, affording different emissions from the bound probe. Conformation‐sensitive probes thus provide a direct link between spectral signal and protein conformation. Finally, the probes also proved useful for ex vivo fluorescence imaging by multiphoton excitation.
Hypnosis with a blind 55‐year‐old female with dental phobia requiring periodontal treatment and extraction
Authors: Gow Michael A.
Published: May 2006

Presenting problem: Jo is a 55‐year‐old female who has a phobia of dental treatment. She has been completely blind since birth and requires periodontal treatment and subsequent extraction.

Aim: Treat Jo's periodontal condition and decrease her phobia and fear of treatment by using hypnosis as an adjunct to basic anxiety management techniques.

Methods: In surgery, medical, dental and phobia history explored. Pre‐treatment questionnaires assessed dental anxiety, reasons for anxiety, and ascertained management options. Post‐treatment questionnaires assessed changes in dental anxiety and attitudes. Anxiety management techniques included Tell/Show/Do and hypnosis.

Results: Pre‐treatment questionnaire revealed high level anxiety and anticipation of pain during future dental treatment. Following hypnotic intervention facilitating periodontal intervention and subsequent extraction, repeated questionnaires revealed significant reduction in anxiety and anticipation of pain.

Conclusion: Hypnosis seems to have been successful as an adjunct in achieving the initial aim. Copyright © 2006 British Society of Experimental & Clinical Hypnosis. Published by John Wiley & Sons, Ltd.
Mechanisms of and Effect of Coadsorption on Water Dissociation on an Oxygen Vacancy of the MgO(100) Surface
Authors: Wang Yan , Nguyen Hung N. , Truong Thanh N.
Published: May 2006

The dissociation mechanism of a water molecule at an oxygen vacancy on the MgO(100) surface was studied by using the embedded cluster method at the DFT/B3 LYP level, while the energetic information was refined by using the IMOMO method at the CCSD level. We found that a water molecule initially adsorbs on one of the magnesium ions surrounding the vacancy site with a binding energy of 15.98 kcal mol−1. It then can dissociate on the MgO(100) surface along two possible dissociation pathways. One pathway produces a hydroxyl group bonded to the original magnesium with a proton filling the vacancy via a transition state with a barrier of 4.67 kcal mol−1 relative to the adsorbed water configuration. The other pathway yields two hydroxy groups; the hydroxy group originally belonging to the water molecule fills the vacancy, while the hydrogen atom binds with the surface oxygen to form the other hydroxy group. Hydrogen atoms of these hydroxy groups can recombine to form a hydrogen molecule and the surface is healed. Although the barrier (14.09 kcal mol−1) of the rate‐controlling step of the latter pathway is higher than that of the former one, the energies of all of its stationary points are lower than that of the separated reactants (H2O+cluster). The effects of water coadsorption are modeled by placing an additional water molecule near the active center, which suggests that the more coadsorbed water molecules further stabilize the hydroxy species and prevent the hydrogen molecule formation through the latter pathway. The results support the photoemission spectral evidence of water dissociation on the defective MgO(100) surface at low water coverage.
Synthetic aperture radar applying PN sequences
Authors: Furuno Takayoshi , Ikuno Hiroyoshi
Published: May 2006

In order to perform recognition of a moving target with a satellite‐borne synthetic aperture radar, the use of a PN (Pseudorandom Noise) sequence is proposed. By employing two different PN sequences alternately, in‐pulse modulation is performed. The pulse wave transmitted from a satellite with a specified PRF (Pulse Reception Frequency) is used for illumination of several targets and the received backscattered wave signal is demodulated with the same PN sequences as those for the transmitted pulse wave. The demodulated signal components have substantial correlation with the signal components from the target, so that pseudosignals leaking from adjacent pulses and moving clutter can be suppressed sufficiently. The signal components demodulated by the newly proposed PN sequence are aperture‐synthesized in a manner similar to that used in the conventional method. The target is approximated by a point target and the difference between the front and back pulse demodulated signals of the backscatter from the target is subjected to the wavelet transform. In this way, the recognition of stationary and moving targets and identification of the radial speed of moving targets are possible. © 2006 Wiley Periodicals, Inc. Electron Comm Jpn Pt 1, 89(11): 12–23, 2006; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/ecja.20290
Broadband lossy conductor wall processing using lumped constant circuit and recursive formulas on FDTD method
Authors: Takata Masaaki , Iida Yukio
Published: May 2006

A practical conductor boundary processing method using the surface impedance boundary condition in the FDTD method is presented. In the present method, the surface impedance on the conductor is first replaced by an approximate equation. This approximation can easily suppress the approximation errors in the frequency range of interest in the analysis. Next, by means of inverse Laplace transform, the approximate equation is expressed in the time domain. In this way, the problem can be replaced by the excellent recursive operation previously proposed and a new update equation can be derived. Also, as a confirmation of the validity of the present conductor boundary processing method, an FDTD analysis is carried out for propagation of the TEM wave between the conductors and the results are compared with the theoretical values of the analysis model. As a result, remarkable agreement with the theoretical values is obtained over a broad frequency range. © 2006 Wiley Periodicals, Inc. Electron Comm Jpn Pt 2, 89(6): 8–13, 2006; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/ecjb.20172
Glacier development and topographic context
Authors: López‐Moreno J. I. , Nogués‐Bravo D. , Chueca‐Cía J. , Julián‐Andrés A.
Published: May 2006

This paper analyses the topographic context of the remaining glaciated areas in the Maladeta Massif (Central Spanish Pyrenees). These ice‐covered surfaces have been incorporated into a geographic information system (GIS) in an attempt at correlating the presence of ice with a range of topographic variables obtained from a digital elevation model. The use of generalized additive models and binary regression tree models enabled us (i) to quantify the spatial variability in the distribution of glaciers attributable to characteristics of the local terrain, (ii) to investigate the interaction between the variables that account for the ice cover distribution and (iii) to map the probability of glacier development. Our results show that although the development of glaciers depends on regional climate conditions, the topographic context is of paramount importance in determining the location, extent, shape and recent evolution of each glacial body. Thus, the joint effect of altitude, exposure to incoming solar radiation, slope and mean curvature is able to explain more than 70 per cent of the observed variance. Copyright © 2006 John Wiley & Sons, Ltd.