bluuebunny/crossref_metadata_2025 huggingface dataset:
Hogarth, Egan, Dickens, and the Making of an Urban Aesthetic
Authors: Sen Sambudha
Published: July 2008

This essay tracks the making of an urban aesthetic as it developed from Hogarth's Industry and Idleness to Dickens's Oliver Twist. It argues that the urban aesthetic works in these texts to both contain and express the internal differences of the metropolis. It focuses on the ways in which the juxtapositional possibilities produced by the urban aesthetic affected such basic features of the novel as plot and characterization.
Rituximab in relapsing Graves' disease, a phase II study
Authors: Heemstra Karen A , Toes Rene E , Sepers Jan , Pereira Alberto M , Corssmit Eleonora P , Huizinga Tom W J , Romijn Johannes A , Smit Johannes W
Published: July 2008

Objective

Conventional therapies for Graves' disease, consisting of medical therapy or radioiodine are unsatisfactory, because of limited efficacy and adverse events. Interventions aimed at the underlying autoimmune pathogenesis of Graves' disease may be worthwhile to explore. We therefore performed a prospective, 26-week phase II study with open-ended observational extension to assess the efficacy of rituximab in patients with recurrent Graves' disease.

Design

We performed a prospective, 26-week phase II study with open-ended observations.

Methods

Thirteen patients with relapsing Graves' disease (9 females and 4 males, age 39.5±9.5 years) received 2 dosages of rituximab 1000 mg i.v. with a 2-week interval. Before administration and on several periods after the administration of TSH, free thyroxine (FT4), thyrotropin binding inhibitory immunoglobulins (TBII) and the proportion of CD19 and MS4A1 positive peripheral blood mononuclear cells were measured.

Results

The proportion of MS4A1 positive lymphocytes decreased in all patients from 5.8% at baseline to 1.4% at 26 weeks (P=0.007). Four patients with high initial FT4 levels did not respond to treatment. All remaining patients had a decrease in FT4 levels at 26 weeks (P=0.001) and an increase in TSH levels (P=0.011). TBII decreased in all remaining patients (P=0.003). At a follow-up time of 14–27 months, nine of these patients were still euthyroid with normal FT4 (P<0.001) and TSH levels (P=0.008).

Conclusions

The present study results suggest a beneficial role of rituximab in mild relapsing Graves' disease. A subsequent randomized controlled trial with rituximab is recommended.
Stem cell transplantation in the treatment of gastrointestinal diseases
Authors: Hagymási Krisztina , Molnár Béla , Tulassay Zsolt
Published: July 2008

Az őssejtek önmegújító képességű, egy vagy több differenciált sejttípus létrehozására képes sejtek. Multipotensek, könnyű kinyerésük révén a sejt- és génterápia célpontjai lehetnek a jövőben. Felnőtt mesenchymalis, neuronalis, epidermalis, haematopoeticus őssejtek alkalmazása előnyös lehet szív- (myocardialis infarctus), csont- (osteoarthritis), idegbetegségek (Parkinson-, Alzheimer-kór), hematológiai kórképek (haemophilia, thrombocytopenia) kezelésében. A szerzők a gyomor-bél rendszer betegségeiben történt alkalmazásukkal kapcsolatos kis-, de növekvő számú ismereteket tekintik át. A haematopoeticus őssejtátültetés eredményes volt kezelésre nem reagáló Crohn-betegekben, coeliakiás betegek bizonyos csoportjában. A máj kötőszövetes elfajulásának megelőzésére mesenchymalis őssejteket alkalmaztak sikerrel. A haematopoeticus őssejt-transzplantációs kezelésre nem reagáló autoimmun gyomor-bél rendszeri betegségekben ígéretes lehetőség lehet. További terápiás célpontok lehetnek az autoimmun májbetegségek: autoimmun hepatitis, primer biliaris cirrhosis, primer sclerotizáló cholangitis. Jól tervezett multicentrikus prospektív vizsgálatok szükségesek az esettanulmányok és a kisszámú klinikai vizsgálat során tapasztalt lehetőségek bizonyítására.
Mantle cell lymphoma: case report
Authors: Méhes Leonóra , Telek Béla , Udvardy Miklós , Schlammadinger Ágota , Rejtő László
Published: July 2008

A köpenysejtes lymphoma (MCL) mérsékelten agresszív betegség, amely kemoimmunoterápiával nem gyógyítható. A medián túlélés rövid, mintegy három év. Többnyire előrehaladott stádiumban ismerik fel. A csontvelő a betegek felében, a gastrointestinalis traktus a negyedükben érintett, leukémiás transzformáció 25%-ban fordul elő. A malignus sejtek B-sejt-eredetűek és CD5-pozitívak, jellemző a ciklin-D1-expresszió. A kezelésben kombinált kemoterápia, kemoimmunoterápia, valamint autológ perifériás őssejt- (és allogén) transzplantáció jöhet szóba. A bemutatott két beteg esetében, az optimális kezdeti terápia hiánya ellenére, tartós túlélés volt elérhető. Az alkalmazott komplex kezelés (kemoimmunoterápia, sugárkezelés, sebészi beavatkozás, autológ őssejt-transzplantáció) ugyanis 80, illetve 90 hónapig tartó túlélést eredményezett. A két beteg kórtörténetének ismertetése mellett a szerzők áttekintik a köpenysejtes lymphoma korszerű kezelésének mai lehetőségeit.
Regulation of endocrine and paracrine sources of Igfs and Gh receptor during compensatory growth in hybrid striped bass (Morone chrysops×Morone saxatilis)
Authors: Picha Matthew E , Turano Marc J , Tipsmark Christian K , Borski Russell J
Published: July 2008

Compensatory growth (CG) is a period of growth acceleration that exceeds normal rates after animals are alleviated of certain growth-stunting conditions. In hybrid striped bass (HSB, Morone chrysops×Morone saxatilis), 3 weeks of complete feed restriction results in a catabolic state that, when relieved, renders a subsequent phase of CG. The catabolic state was characterized by depressed levels of hepatic Type I and II GH receptor (ghr1, ghr2) and igf1 mRNA, along with considerable decreases in plasma Igf1. The state of catabolism also resulted in significant declines in hepatic igf2 mRNA and in circulating 40 kDa Igf-binding protein (Igfbp). Skeletal muscle expression of ghr2 mRNA was significantly increased. Upon realimentation, specific growth rates (SGRs) were significantly higher than sized-matched controls, indicating a period of CG. Hepatic ghr1, ghr2, igf1 and igf2 mRNA levels along with plasma Igf1 and 40 kDa Igfbp increased rapidly during realimentation. Plasma Igf1 and total hepatic igf2 mRNA were significantly correlated to SGR throughout the study. Skeletal muscle igf1 mRNA also increased tenfold during CG. These data suggest that endocrine and paracrine/autocrine components of the GH–Igf axis, namely igf1, igf2, and ghr1 and ghr2, may be involved in CG responses in HSB, with several of the gene expression variables exceeding normal levels during CG. We also demonstrate that normalization of hepatic mRNA as a function of total liver production, rather than as a fraction of total RNA, may be a more biologically appropriate method of quantifying hepatic gene expression when using real-time PCR.
Using field data and weight of evidence to develop water quality criteria
Authors: Cormier Susan M , Paul John F , Spehar Robert L , Shaw-Allen Patricia , Berry Walter J , Suter Glenn W
Published: July 2008

In the United States, ambient aquatic life water quality criteria are derived using guidelines developed in 1985 that include a clear and consistent methodology using data from standard toxicity tests. The methodology from these guidelines has been successful, but a broader methodology is needed because some effects of pollutants do not lend themselves to conventional toxicity testing. Criterion assessment is proposed as that methodology. In criterion assessment, a specific environmental goal is translated into a measurable benchmark of effect that is used together with a modeled exposure—response relationship to estimate a range of exposures that will achieve the specific goal. The model of the exposure—response relationships and the benchmark effect are developed from field data and laboratory data using multiple analytical methods. Then the model is solved for the effect, thereby estimating the criterion, an upper threshold for acceptable exposures. The resulting candidate criteria are synthesized to select criteria and other benchmark values, such as remedial goals. The criterion assessment process is illustrated using the US Environmental Protection Agency Framework for Developing for Suspended and Bedded Sediments Water Quality Criteria, which recommends developing alternative candidate criterion values and then evaluating them to select a final criterion. Candidate criteria may be derived from models of field observations, field manipulations, laboratory tests, or empirical and theoretical models. Final selection of a criterion uses a weight-of-evidence comparison that engenders confidence because causal associations are confirmed on the basis of different assumptions, independent data sets, and varied statistical methods, thereby compensating for the concerns raised by individual studies and methods. Thus, it becomes possible to specify criteria for agents with biological or physical modes of action, as well as those with chemical modes of action, to best achieve environmental goals.
Predicted Impacts From Offshore Produced-Water Discharges on Hypoxia in the Gulf of Mexico
Authors: Bierman Victor J. , Hinz Scott C. , Justic Dubravko , Scavia Don , Veil John A. , Satterlee Kent , Parker Michael E. , Wilson Scott
Published: July 2008

Summer hypoxia (dissolved oxygen<2 mg/L) in the bottom waters of the northern Gulf of Mexico has received considerable scientific and policy attention because of potential ecological and economic impacts. This hypoxic zone forms off the Louisiana coast each summer and has increased from an average of 8,300 km2 in 1985–1992 to over 16,000 km2 in 1993–2001, reaching a record 22,000 km2 in 2002. The almost threefold increase in nitrogen load from the Mississippi River Basin (MRB) to the Gulf since the middle of the last century is the primary external driver for hypoxia.

A goal of the 2001 Federal Action Plan is to reduce the 5-year running average size of the hypoxic zone to below 5,000 km2 by 2015. After the Action Plan was developed, a new question arose as to whether sources other than the MRB may also contribute significant quantities of oxygen-demanding substances. One very visible potential source is the hundreds of offshore oil and gas platforms located within or near the hypoxic zone, many of which discharge varying volumes of produced water.

The objectives of this study were to assess the incremental impacts of produced water discharges on dissolved oxygen in the northern Gulf of Mexico, and to evaluate the significance of these discharges relative to loadings from the MRB. Predictive simulations were conducted with three existing models of Gulf hypoxia using produced water loads from an industry study. Scenarios were designed that addressed loading uncertainties, settleability of suspended constituents, and different assumptions on delivery locations for the produced water loads. Model results correspond to the incremental impacts of produced water loads, relative to the original model results, which included only loads from the MRB.

The predicted incremental impacts of produced water loads on dissolved oxygen in the northern Gulf of Mexico from all three models were small. Even considering the predicted ranges between lower- and upper-bound results, these impacts are likely to be within the errors of measurement for bottomwater dissolved oxygen and hypoxic area at the spatial scale of the entire hypoxic zone.
The Evolution of Inert-Gas Systems on SBM FPSOs: The Problem of Venting and a Straightforward Solution
Authors: de Vos Dirk , Duddy Michael , Bronneburg Jos
Published: July 2008

As a floating production, storage, and offloading vessel (FPSO) continually loads stabilized crude oil to the cargo tanks, the inert-gas (IG) blanket within the tanks is compressed. At a certain pressure, below that which could cause damage to the vessel structure, this mixture of now IG and volatile organic compounds (VOCs), emanated from the loaded crude, must be vented safely to atmosphere by some means.

From the very first FPSO that Single Buoy Moorings (SBM) operated, the FPSO II in 1980, errant gas (IG) has resulted in a number of emergency shutdowns (ESDs) while venting the cargo tanks during calm weather. With no wind to disperse the heavier-than-air gas, the result is the mixture falling onto the vessel main deck or the process modules, triggering the FPSO gas-detection system and subsequently causing an ESD. The cost can quickly become considerable because of loss or delay of production in this manner.

More importantly, while venting the cargo tanks, personnel are relocated to a safe area to ensure their safety, and any hot-work being undertaken is postponed. Crane and helicopter operations also are suspended. There is, of course, a cost associated with the loss of personnel productivity during these events.

To prevent reoccurrence of IG venting-related incidents, a number of operational measures are used. These usually consist of

Delaying venting during low-wind periods (<2 ms) Employing the downstream vent mast (if two are fitted, one on either side of the vessel) Monitoring the gas concentration by way of the gas-detection system

As a high concentration is attained [usually approximately 40% of the lower-explosive limit (LEL)], venting is stopped until the gas has been dispersed. Typically, the alarm is activated at 20% LEL, and the executive action (in this case, an ESD) is set at 60% LEL.

With FPSOs becoming larger, and production rates correspondingly so (sometimes more than 300,000 B/D), the financial penalties resulting from an unplanned shutdown are even more significant. Although using operational means can be a successful way of mitigating both the safety and production risks associated with IG venting, a system that would obviate the need for such procedures has been sought by SBM since their first operating FPSO, more than 25 years ago.

This paper describes the evolution of the IG arrangements on board SBM's units, past and present systems that have been used with varying degrees of success and the recent (July 2005) retrofit of an IG eductor to 2 SBM FPSOs operating west of Africa. The details of the patented IG eductor, from conception, design, safety studies, construction, installation, and operational success, are also presented.
Economics of GTL Plants
Authors: Al-Saadoon Faleh T.
Published: July 2008

A unique approach for assessing the economic viability of gas-to-liquid (GTL) plants is used. The capital expenditures (capex) are based on the production of 1 bbl of hydrocarbon liquid per day (BLPD), whereas the annual operating expenditures (opex) are expressed as percentages of capex. Both expenditures cover the range of costs envisioned by various vendors and investigators. It is assumed that the overall thermal efficiency of GTL plants is approximately 60% and that the plant operates 334 days per year. The capital expenditures used in this study are U.S. $20,000, $25,000, $30,000, $35,000, and $40,000 per BLPD. (Note: all expenditures in this paper are stated in U.S. dollars.) The annual operating expenditures used are 5, 6, and 7% of capex. Thus, the range of operating expenditures used is $3.03 to $8.48 per barrel of liquid hydrocarbon produced.

Two measures of profitability are used in assessing the economic viability of GTL plants, namely rate of return (ROR) and undis-counted payout time (POT). Rates of return used in this study are 10, 15, and 20%, whereas the payout times used are 4, 5, 6, 7, and 8 years. Construction periods of 3 and 4 years are considered in the analysis. A general survey of GTL processes is also included.
A Model To Predict Liquid Holdup and Pressure Gradient of Near-Horizontal Wet-Gas Pipelines
Authors: Fan Yongqian , Wang Qian , Zhang Hongquan , Danielson Thomas J. , Sarica Cem
Published: July 2008

A mechanistic two-fluid model with new closure relationships is proposed to predict liquid holdup and pressure gradient of stratified flow. The proposed closure relationships include correlations of wetted-wall fraction factor, liquid-wall friction factor, and interfacial-friction factor. An iterative calculation procedure is implemented to solve for liquid holdup and pressure gradient for a given set of operating conditions, pipe geometry, and fluid properties.

Two sets of facilities, a small-scale facility with 51-mm internal diameter (ID) and a large-scale facility with 150-mm-ID test sections, were used to tune the model. Superficial gas and liquid velocities were varied from 5 to 25 m/s and 0.00025 to 0.03 m/s, respectively, in the small-scale facility while they were varied from 7.5 to 21 m/s and 0.005 to 0.05 m/s, respectively, in the large-scale facility. The pipe inclination angle varied from −2 to 2°. The liquid holdup was ranged between 0.003 and 0.12, emphasizing the low-liquid-loading two-phase flow.

The tuned model performance was then benchmarked against the high-pressure (up to 90 bar) SINTEF-stratified flow data. The model predictions agreed well with measured values of liquid holdup and pressure gradient. The comparison between the present model and OLGA® (a commercial transient multiphaseflow simulator by Scandpower Petroleum) performance was also presented.
SABAE‐HW: An Enhanced Water Balance Prediction in the Canadian Land Surface Scheme Compared with Existing Models
Authors: Loukili Youssef , Woodbury Allan D. , Snelgrove Kenneth R.
Published: July 2008

The Canadian Land Surface Scheme (CLASS) is a numerical model pioneered at the Canadian Atmospheric Environment Service by Verseghy (1991) and Verseghy et al. (1993) to evaluate the vertical transfer of energy and water between the atmosphere and three surface soil layers. This article introduces SABAE‐HW (soil atmosphere boundary, accurate evaluations of heat and water), a new model built using the modeling framework of CLASS version 2.6 that allows a user to specify depth and number of soil layers. The physically based calculations of heat and moisture transfer are adequately extended in the new code to fit the desired refined mesh. The generalized minimal residual (GMRES) iterative method is used to resolve new soil heat flux terms. Moreover, a water table lower boundary condition is added to allow eventual coupling with groundwater models. The results of SABAE‐HW are validated for some synthetic runs under real‐like seasonal weather conditions and various soil types. Then the model prediction capability is confirmed for a location within the Assiniboine Delta Aquifer using North American Regional Reanalysis (NARR) atmospheric data. Intercomparisons of results to simulation outputs from CLASS, SHAW, HYDRUS‐1D, and HELP models demonstrate the capability of SABAE‐HW to predict reasonable moisture profiles and water budget terms. Under warm weather conditions, SABAE‐HW and SHAW yield similar water content profiles and bottom drainages. Also, in the freezing–thawing situations, detailed moisture profiles by SABAE‐HW are contrasted to both CLASS and SHAW solutions.
Muscle-Specific IRS-1 Ser→Ala Transgenic Mice Are Protected From Fat-Induced Insulin Resistance in Skeletal Muscle
Authors: Morino Katsutaro , Neschen Susanne , Bilz Stefan , Sono Saki , Tsirigotis Dimitrios , Reznick Richard M. , Moore Irene , Nagai Yoshio , Samuel Varman , Sebastian David , White Morris , Philbrick William , Shulman Gerald I.
Published: July 2008

OBJECTIVE—Insulin resistance in skeletal muscle plays a critical role in the pathogenesis of type 2 diabetes, yet the cellular mechanisms responsible for insulin resistance are poorly understood. In this study, we examine the role of serine phosphorylation of insulin receptor substrate (IRS)-1 in mediating fat-induced insulin resistance in skeletal muscle in vivo.

RESEARCH DESIGN AND METHODS—To directly assess the role of serine phosphorylation in mediating fat-induced insulin resistance in skeletal muscle, we generated muscle-specific IRS-1 Ser302, Ser307, and Ser612 mutated to alanine (Tg IRS-1 Ser→Ala) and IRS-1 wild-type (Tg IRS-1 WT) transgenic mice and examined insulin signaling and insulin action in skeletal muscle in vivo.

RESULTS—Tg IRS-1 Ser→Ala mice were protected from fat-induced insulin resistance, as reflected by lower plasma glucose concentrations during a glucose tolerance test and increased insulin-stimulated muscle glucose uptake during a hyperinsulinemic-euglycemic clamp. In contrast, Tg IRS-1 WT mice exhibited no improvement in glucose tolerance after high-fat feeding. Furthermore, Tg IRS-1 Ser→Ala mice displayed a significant increase in insulin-stimulated IRS-1–associated phosphatidylinositol 3-kinase activity and Akt phosphorylation in skeletal muscle in vivo compared with WT control littermates.

CONCLUSIONS—These data demonstrate that serine phosphorylation of IRS-1 plays an important role in mediating fat-induced insulin resistance in skeletal muscle in vivo.
Activation of NF-E2–Related Factor-2 Reverses Biochemical Dysfunction of Endothelial Cells Induced by Hyperglycemia Linked to Vascular Disease
Authors: Xue Mingzhan , Qian Qingwen , Adaikalakoteswari Antonysunil , Rabbani Naila , Babaei-Jadidi Roya , Thornalley Paul J.
Published: July 2008

OBJECTIVE—Sulforaphane is an activator of transcription factor NF-E2–related factor-2 (nrf2) that regulates gene expression through the promoter antioxidant response element (ARE). Nrf2 regulates the transcription of a battery of protective and metabolic enzymes. The aim of this study was to assess whether activation of nrf2 by sulforaphane in human microvascular endothelial cells prevents metabolic dysfunction in hyperglycemia.

RESEARCH DESIGN AND METHODS—Human microvascular HMEC-1 endothelial cells were incubated in low and high glucose concentrations (5 and 30 mmol/l, respectively), and activation of nrf2 was assessed by nuclear translocation. The effects of sulforaphane on multiple pathways of biochemical dysfunction, increased reactive oxygen species (ROS) formation, hexosamine pathway, protein kinase C (PKC) pathway, and increased formation of methylglyoxal were assessed.

RESULTS—Activation of nrf2 by sulforaphane induced nuclear translocation of nrf2 and increased ARE-linked gene expression, for example, three- to fivefold increased expression of transketolase and glutathione reductase. Hyperglycemia increased the formation of ROS—an effect linked to mitochondrial dysfunction and prevented by sulforaphane. ROS formation was increased further by knockdown of nrf2 and transketolase expression. This also abolished the counteracting effect of sulforaphane, suggesting mediation by nrf2 and related increase of transketolase expression. Sulforaphane also prevented hyperglycemia-induced activation of the hexosamine and PKC pathways and prevented increased cellular accumulation and excretion of the glycating agent methylglyoxal.

CONCLUSIONS—We conclude that activation of nrf2 may prevent biochemical dysfunction and related functional responses of endothelial cells induced by hyperglycemia in which increased expression of transketolase has a pivotal role.
Spontaneous Diabetes in Hemizygous Human Amylin Transgenic Mice That Developed Neither Islet Amyloid nor Peripheral Insulin Resistance
Authors: Wong Winifred P.S. , Scott David W. , Chuang Chia-Lin , Zhang Shaoping , Liu Hong , Ferreira Athena , Saafi Etuate L. , Choong Yee Soon , Cooper Garth J.S.
Published: July 2008

OBJECTIVES—We sought to 1) Determine whether soluble-misfolded amylin or insoluble-fibrillar amylin may cause or result from diabetes in human amylin transgenic mice and 2) determine the role, if any, that insulin resistance might play in these processes.

RESEARCH DESIGN AND METHODS—We characterized the phenotypes of independent transgenic mouse lines that display pancreas-specific expression of human amylin or a nonaggregating homolog, [25,28,29Pro]human amylin, in an FVB/n background.

RESULTS—Diabetes occurred in hemizygous human amylin transgenic mice from 6 weeks after birth. Glucose tolerance was impaired during the mid- and end-diabetic phases, in which progressive β-cell loss paralleled decreasing pancreatic and plasma insulin and amylin. Peripheral insulin resistance was absent because glucose uptake rates were equivalent in isolated soleus muscles from transgenic and control animals. Even in advanced diabetes, islets lacked amyloid deposits. In islets from nontransgenic mice, glucagon and somatostatin cells were present mainly at the periphery and insulin cells were mainly in the core; in contrast, all three cell types were distributed throughout the islet in transgenic animals. [25,28,29Pro]human amylin transgenic mice developed neither β-cell degeneration nor glucose intolerance.

CONCLUSIONS—Overexpression of fibrillogenic human amylin in these human amylin transgenic mice caused β-cell degeneration and diabetes through mechanisms independent from both peripheral insulin resistance and islet amyloid. These findings are consistent with β-cell death evoked by misfolded but soluble cytotoxic species, such as those formed by human amylin in vitro.
Hepatocyte Growth Factor Enhances Engraftment and Function of Nonhuman Primate Islets
Authors: Fiaschi-Taesch Nathalie M. , Berman Dora M. , Sicari Brian M. , Takane Karen K. , Garcia-Ocaña Adolfo , Ricordi Camillo , Kenyon Norma S. , Stewart Andrew F.
Published: July 2008

OBJECTIVE—Adenoviral delivery of hepatocyte growth factor (HGF) to rodent islets improves islet graft survival and function, markedly reducing the number of islets required to achieve glucose control. Here, we asked whether these prior observations in rodent models extend to nonhuman primate (NHP) islets.

RESEARCH DESIGN AND METHODS—NHP islets were transduced with murine (Ad.mHGF) or human (Ad.hHGF) adenoviral HGF (Ad.HGF) at low multiplicity of infection and studied in vitro. To study the function of Ad.HGF-transduced NHP islets in vivo, a renal subcapsular marginal mass islet transplant model was developed in streptozotocin-induced diabetic NOD-SCID mice.

RESULTS—Baseline glucose values were 454.7 ± 11.3 mg/dl (n = 7). Transplant of 500 NHP islet equivalents (IE) had only a marginal effect on blood glucose (369.1 ± 9.7 mg/dl, n = 5). In striking contrast, 500 NHP IE transduced with Ad.mHGF promptly and continuously corrected blood glucose (142.0 ± 6.2 mg/dl, n = 7) for the 6-week duration of the experiment. Unilateral nephrectomy resulted in an immediate return of glucose to baseline diabetic levels. Interestingly, adenoviral DNA, as well as mouse HGF (mHGF) mRNA derived from the adenovirus, were present for 42 days posttransplantation. Surprisingly, transplant of 500 IE with Ad.hHGF, as compared with Ad.mHGF, resulted in only marginal correction of blood glucose, suggesting that human HGF is less efficient than mHGF in this system.

CONCLUSIONS—These studies demonstrate that mHGF markedly improves islet transplant outcomes in the highest preclinical species examined to date. HGF has promise as an agent that can improve islet mass and function in transplant models and likely in other models of types 1 and 2 diabetes.
Sulfasalazine Blocks the Development of Tactile Allodynia in Diabetic Rats
Authors: Berti-Mattera Liliana N. , Kern Timothy S. , Siegel Ruth E. , Nemet Ina , Mitchell Rochanda
Published: July 2008

OBJECTIVE—Diabetic neuropathy is manifested either by loss of nociception (painless syndrome) or by mechanical hyperalgesia and tactile allodynia (pain in response to nonpainful stimuli). While therapies with vasodilators or neurotrophins reverse some functional and metabolic abnormalities in diabetic nerves, they only partially ameliorate neuropathic pain. The reported link between nociception and targets of the anti-inflammatory drug sulfasalazine prompted us to investigate its effect on neuropathic pain in diabetes.

RESEARCH DESIGN AND METHODS—We examined the effects of sulfasalazine, salicylates, and the poly(ADP-ribose) polymerase-1 inhibitor PJ34 on altered nociception in streptozotocin-induced diabetic rats. We also evaluated the levels of sulfasalazine targets in sciatic nerves and dorsal root ganglia (DRG) of treated animals. Finally, we analyzed the development of tactile allodynia in diabetic mice lacking expression of the sulfasalazine target nuclear factor-κB (NF-κB) p50.

RESULTS—Sulfasalazine completely blocked the development of tactile allodynia in diabetic rats, whereas relatively minor effects were observed with other salicylates and PJ34. Along with the behavioral findings, sciatic nerves and DRG from sulfasalazine-treated diabetic rats displayed a decrease in NF-κB p50 expression compared with untreated diabetic animals. Importantly, the absence of tactile allodynia in diabetic NF-κB p50−/− mice supported a role for NF-κB in diabetic neuropathy. Sulfasalazine treatment also increased inosine levels in sciatic nerves of diabetic rats.

CONCLUSIONS—The complete inhibition of tactile allodynia in experimental diabetes by sulfasalazine may stem from its ability to regulate both NF-κB and inosine. Sulfasalazine might be useful in the treatment of nociceptive alterations in diabetic patients.
Common Variants in CDKAL1, CDKN2A/B, IGF2BP2, SLC30A8, and HHEX/IDE Genes Are Associated With Type 2 Diabetes and Impaired Fasting Glucose in a Chinese Han Population
Authors: Wu Ying , Li Huaixing , Loos Ruth J.F. , Yu Zhijie , Ye Xingwang , Chen Lihua , Pan An , Hu Frank B. , Lin Xu
Published: July 2008

OBJECTIVE— Genome-wide association studies have identified common variants in CDKAL1, CDKN2A/B, IGF2BP2, SLC30A8, HHEX/IDE, EXT2, and LOC387761 loci that significantly increase the risk of type 2 diabetes. We aimed to replicate these observations in a population-based cohort of Chinese Hans and examine the associations of these variants with type 2 diabetes and diabetes-related phenotypes.

RESEARCH DESIGN AND METHODS— We genotyped 17 single nucleotide polymorhisms (SNPs) in 3,210 unrelated Chinese Hans, including 424 participants with type 2 diabetes, 878 with impaired fasting glucose (IFG), and 1,908 with normal fasting glucose.

RESULTS— We confirmed the associations between type 2 diabetes and variants near CDKAL1 (odds ratio 1.49 [95% CI 1.27–1.75]; P = 8.91 × 10−7) and CDKN2A/B (1.31 [1.12–1.54]; P = 1.0 × 10−3). We observed significant association of SNPs in IGF2BP2 (1.17 [1.03–1.32]; P = 0.014) and SLC30A8 (1.12 [1.01–1.25]; P = 0.033) with combined IFG/type 2 diabetes. The SNPs in CDKAL1, IGF2BP2, and SLC30A8 were also associated with impaired β-cell function estimated by homeostasis model assessment of β-cell function. When combined, each additional risk allele from CDKAL1-rs9465871, CDKN2A/B-rs10811661, IGF2BP2-rs4402960, and SLC30A8-rs13266634 increased the risk for type 2 diabetes by 1.24-fold (P = 2.85 × 10−7) or for combined IFG/type 2 diabetes by 1.21-fold (P = 6.31 × 10−11). None of the SNPs in EXT2 or LOC387761 exhibited significant association with type 2 diabetes or IFG. Significant association was observed between the HHEX/IDE SNPs and type 2 diabetes in individuals from Shanghai only (P < 0.013) but not in those from Beijing (P > 0.33).

CONCLUSIONS— Our results indicate that in Chinese Hans, common variants in CDKAL1, CDKN2A/B, IGF2BP2, and SLC30A8 loci independently or additively contribute to type 2 diabetes risk, likely mediated through β-cell dysfunction.
Impaired Collateral Recruitment and Outward Remodeling in Experimental Diabetes
Authors: van Golde Jolanda M. , Ruiter Matthijs S. , Schaper Nicolaas C. , Vöö Stefan , Waltenberger Johannes , Backes Walter H. , Post Mark J. , Huijberts Maya S.
Published: July 2008

OBJECTIVE—In this study, the effect of chronic hyperglycemia on acute ligation-induced collateral vasodilation, on monocyte chemotaxis, and on structural outward remodeling of collaterals was investigated.

RESEARCH DESIGN AND METHODS—Femoral artery ligation was performed 8 weeks after alloxan or saline treatment in New Zealand White rabbits. Angiography was performed directly, 1 and 3 weeks after ligation. These angiographic recordings were used to quantify number of collaterals, lumen, and blood volume index. Reactive hyperemia response was tested by intramuscular laser Doppler measurements. Subsequently, blood was sampled from the aorta for monocyte chemotaxis.

RESULTS—Ligation resulted in markedly lower acute collateral vasodilation in diabetic compared with control rabbits. Also, hyperemic vasodilatory response to local ischemia was impaired in diabetic rabbits. This difference persisted at 1 and 3 weeks after ligation, with a lower number of visible collaterals. In addition, the collateral lumen was markedly lower in diabetic rabbits after the maturation phase. Likewise, a reduced blood volume index in the region of growing collaterals was observed in diabetic animals. The monocyte migration toward vascular endothelial growth factor-A and monocyte chemotactic protein-1 was strongly reduced in diabetic rabbits.

CONCLUSIONS—This study demonstrates that chronic hyperglycemia negatively affects the different phases of arteriogenesis: 1) impaired shear induced vasodilatation; 2) impaired outward collateral growth, reflected in the number of collaterals and blood volume index; and 3) inhibition of monocyte chemotaxis. Impairments were most evident in the acute phase of arteriogenesis. Therapies aimed at restoring acute collateral recruitment, such as vasodilators, may be of interest to improve collateral function in diabetes.
Simultaneous Islet and Kidney Transplantation in Seven Patients With Type 1 Diabetes and End-Stage Renal Disease Using a Glucocorticoid-Free Immunosuppressive Regimen With Alemtuzumab Induction
Authors: Tan Jianming , Yang Shunliang , Cai Jinquan , Guo Junqi , Huang Lianghu , Wu Zhixian , Chen Jin , Liao Lianming
Published: July 2008

OBJECTIVE—The aim of this study was to evaluate the efficiency and safety of simultaneous islet and kidney transplantation in patients with type 1 diabetes and end-stage renal disease using a glucocorticoid-free immunosuppressive regimen with alemtuzumab induction.

RESEARCH DESIGN AND METHODS—Seven patients with type 1 diabetes and end-stage renal failure were transplanted with allogenic islets and kidneys procured from brain-dead donors. To prevent organ rejection, patients received alemtuzumab for induction immunosuppression, followed by sirolimus and tacrolimus. No glucocorticoids were given at any time.

RESULTS—The median duration of follow-up was 18.3 months (range 13–31). Kidney survival was 100%. Four patients became insulin independent at 1 year. The other three reduced insulin use to less than 25% of the amount required before transplantation. Serum C-peptide levels were significantly greater posttransplant in all patients, indicating continued islet function. No major procedure-related complications were observed.

CONCLUSIONS—Our results demonstrate that a steroid-free immunosuppressive regimen consisting of alemtuzumab, sirolimus, and tacrolimus is feasible for simultaneous islet and kidney transplantation. The question of whether this induction regimen is superior to more standard induction deserves large studies.
Plasma Fetuin-A Levels and the Risk of Type 2 Diabetes
Authors: Stefan Norbert , Fritsche Andreas , Weikert Cornelia , Boeing Heiner , Joost Hans-Georg , Häring Hans-Ulrich , Schulze Matthias B.
Published: July 2008

OBJECTIVE—The liver-secreted protein fetuin-A induces insulin resistance in animals, and circulating fetuin-A is elevated in insulin resistance and fatty liver in humans. We investigated whether plasma fetuin-A levels predict the incidence of type 2 diabetes in a large prospective, population-based study.

RESEARCH DESIGN AND METHODS—A case-cohort study within the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam study comprising 27,548 subjects was designed. We randomly selected a subcohort of 2,500 individuals of whom 2,164 were diabetes free at baseline and had anamnestic, anthropometrical, and metabolic data for analysis. Of the 849 incident diabetic case subjects identified in the full cohort during 7 years of follow-up, 703 remained for analyses after similar exclusions.

RESULTS—Plasma fetuin-A levels were positively associated with diabetes risk after adjustment for age (relative risk [RR] for extreme quintiles 1.75 [95% CI 1.32–2.31]; RR for 10 μg/ml 1.04 [1.03–1.06]). The association remained significant after adjustment for sex, BMI, waist circumference, and lifestyle risk factors (RR for 10 μg/ml 1.03 [1.01–1.06]). Adjustment for glucose, triglycerides, HDL cholesterol, A1C, γ-glutamyltransferase, or high-sensitivity C-reactive protein or mutual adjustment for these biomarkers did not appreciably change this result (RR for 10 μg/ml full adjusted model 1.05 [1.02–1.07]). Furthermore, fetuin-A was associated with increased diabetes risk particularly in individuals with elevated plasma glucose.

CONCLUSIONS—Our data suggest that fetuin-A is an independent risk factor of type 2 diabetes.
Increased Expression of CCL2 in Insulin-Producing Cells of Transgenic Mice Promotes Mobilization of Myeloid Cells From the Bone Marrow, Marked Insulitis, and Diabetes
Authors: Martin Andrea P. , Rankin Sara , Pitchford Simon , Charo Israel F. , Furtado Glaucia C. , Lira Sergio A.
Published: July 2008

OBJECTIVE—To define the mechanisms underlying the accumulation of monocytes/macrophages in the islets of Langerhans.

RESEARCH DESIGN AND METHODS—We tested the hypothesis that macrophage accumulation into the islets is caused by overexpression of the chemokine CCL2. To test this hypothesis, we generated transgenic mice and evaluated the cellular composition of the islets by immunohistochemistry and flow cytometry. We determined serum levels of CCL2 by enzyme-linked immunosorbent assay, determined numbers of circulating monocytes, and tested whether CCL2 could mobilize monocytes from the bone marrow directly. We examined development of diabetes over time and tested whether CCL2 effects could be eliminated by deletion of its receptor, CCR2.

RESULTS—Expression of CCL2 by β-cells was associated with increased numbers of monocytes in circulation and accumulation of macrophages in the islets of transgenic mice. These changes were promoted by combined actions of CCL2 at the level of the bone marrow and the islets and were not seen in animals in which the CCL2 receptor (CCR2) was inactivated. Mice expressing higher levels of CCL2 in the islets developed diabetes spontaneously. The development of diabetes was correlated with the accumulation of large numbers of monocytes in the islets and did not depend on T- and B-cells. Diabetes could also be induced in normoglycemic mice expressing low levels of CCL2 by increasing the number of circulating myeloid cells.

CONCLUSIONS—These results indicate that CCL2 promotes monocyte recruitment by acting both locally and remotely and that expression of CCL2 by insulin-producing cells can lead to insulitis and islet destruction.
Mixed-Meal Tolerance Test Versus Glucagon Stimulation Test for the Assessment of β-Cell Function in Therapeutic Trials in Type 1 Diabetes
Authors: Greenbaum Carla J. , Mandrup-Poulsen Thomas , McGee Paula Friedenberg , Battelino Tadej , Haastert Burkhard , Ludvigsson Johnny , Pozzilli Paolo , Lachin John M. , Kolb Hubert ,   The Type 1 Diabetes Trial Net Research Group and the European C-Peptide Trial Study Group
Published: July 2008

OBJECTIVE—β-Cell function in type 1 diabetes clinical trials is commonly measured by C-peptide response to a secretagogue in either a mixed-meal tolerance test (MMTT) or a glucagon stimulation test (GST). The Type 1 Diabetes TrialNet Research Group and the European C-peptide Trial (ECPT) Study Group conducted parallel randomized studies to compare the sensitivity, reproducibility, and tolerability of these procedures.

RESEARCH DESIGN AND METHODS—In randomized sequences, 148 TrialNet subjects completed 549 tests with up to 2 MMTT and 2 GST tests on separate days, and 118 ECPT subjects completed 348 tests (up to 3 each) with either two MMTTs or two GSTs.

RESULTS—Among individuals with up to 4 years’ duration of type 1 diabetes, >85% had measurable stimulated C-peptide values. The MMTT stimulus produced significantly higher concentrations of C-peptide than the GST. Whereas both tests were highly reproducible, the MMTT was significantly more so (R2 = 0.96 for peak C-peptide response). Overall, the majority of subjects preferred the MMTT, and there were few adverse events. Some older subjects preferred the shorter duration of the GST. Nausea was reported in the majority of GST studies, particularly in the young age-group.

CONCLUSIONS—The MMTT is preferred for the assessment of β-cell function in therapeutic trials in type 1 diabetes.
Prediction of the Onset of Disturbed Eating Behavior in Adolescent Girls With Type 1 Diabetes
Authors: Olmsted Marion P. , Colton Patricia A. , Daneman Denis , Rydall Anne C. , Rodin Gary M.
Published: July 2008

OBJECTIVE—The purpose of this study was to identify predictors of the onset of disturbed eating behavior (DEB) in adolescent girls with type 1 diabetes.

RESEARCH DESIGN AND METHODS—In this prospective study, participants completed the Children's Eating Disorder Examination interview and self-report measures at baseline and at four follow-up assessments over 5 years. Participants were 126 girls with type 1 diabetes, aged 9–13 years at baseline. Of the 101 girls who did not have DEB at baseline, 45 developed DEB during the follow-up period; the 38 for whom data were available for the assessment before onset of DEB were compared with 38 age-matched girls who did not develop DEB. DEB was defined as dieting for weight control, binge eating, self-induced vomiting, or the use of diuretics, laxatives, insulin omission, or intense exercise for weight control.

RESULTS—Logistic regression indicated that a model including BMI percentile, weight and shape concern, global and physical appearance-based self-worth, and depression was significantly associated with DEB onset (χ2 = 46.0, 5 d.f., P < 0.0001) and accounted for 48.2% of the variance.

CONCLUSIONS—Even though scores on the measures were within the published normal range, the onset of DEB was predicted by higher depression and weight and shape concerns and lower global and physical appearance–based self-worth as well as higher BMI percentile 1–2 years earlier compared with those not developing DEB. Early interventions focused on helping girls with diabetes develop positive feelings about themselves, their weight and shape, and their physical appearance may have protective value.
Superior Mesenteric Artery Syndrome in Type 1 Diabetes Masquerading as Gastroparesis
Authors: Meneghini Luigi F. , Hogan Anthony R. , Selvaggi Gennaro
Published: July 2008

OBJECTIVE—To describe and discuss a case of superior mesenteric artery syndrome (SMAS) presenting with gastrointestinal signs and symptoms mistakenly attributed to, and treated as, diabetic gastroparesis.

RESEARCH DESIGN AND METHODS—A case report was compiled describing the clinical presentation, including history and physical examination, evaluation, diagnosis, and treatment of a patient with type 1 diabetes presenting with gastrointestinal complications.

RESULTS—Clinical suspicion combined with the appropriate radiological evaluation led to a diagnosis of SMAS, with classic findings of reduced aortomesenteric angle and distance. Surgical intervention resulted in resolution of symptoms and recovery of glycemic control.

CONCLUSIONS—The possibility of SMAS should be considered in patients with type 1 diabetes presenting with gastrointestinal symptomatology, especially when associated with weight loss.
Timing Is Everything: Age of Onset Influences Long-Term Retinopathy Risk in Type 2 Diabetes, Independent of Traditional Risk Factors
Authors: Wong Jencia , Molyneaux Lynda , Constantino Maria , Twigg Stephen M. , Yue Dennis K.
Published: July 2008

OBJECTIVE—To test the hypothesis that age of type 2 diabetes onset influences inherent susceptibility to diabetic retinopathy, independent of disease duration and degree of hyperglycemia.

RESEARCH DESIGN AND METHODS—Retinopathy data from 624 patients with a type 2 diabetes duration of 20–30 years (group A) were analyzed by stratifying patients according to age of onset of diabetes and glycemic control. Retinopathy status was scored clinically as per a modified Early Treatment Diabetic Retinopathy Study (ETDRS) severity scale. To obviate possible bias due to a higher attrition from comorbidities in those with later-onset diabetes and retinopathy, 852 patients with type 2 diabetes of shorter duration (10–12 years, group B) were similarly studied.

RESULTS—Prevalence and severity of retinopathy was significantly higher in the younger-onset, group A patients. When further stratified according to mean A1C, retinopathy risk remained increased in younger-onset patients. The greatest impact was seen in those with a mean A1C >9% (odds ratio [OR] for retinopathy 16.6, 7.5, and 2.7 for age of diagnosis <45, 45–55, and >55 years, respectively, P = 0.003). By logistic regression, earlier type 2 diabetes onset is associated with increased retinopathy risk, independent of traditional risk factors (OR of retinopathy 1.9, 1.1, and 1 for age of onset <45, 45–55, and >55 years, respectively). Similar results were found in group B patients.

CONCLUSIONS— These data suggest an increased inherent susceptibility to diabetic retinopathy with earlier-onset type 2 diabetes. This further supports the importance of delaying development of diabetes and also implies a need for more stringent metabolic targets for younger individuals.
Glucose Intolerance in Pregnancy and Future Risk of Pre-Diabetes or Diabetes
Authors: Retnakaran Ravi , Qi Ying , Sermer Mathew , Connelly Philip W , Hanley Anthony J.G. , Zinman Bernard
Published: July 2008

OBJECTIVE—The purpose of this study was to test the hypothesis that any degree of abnormal glucose homeostasis detected on antepartum screening for gestational diabetes mellitus (GDM) should be associated with an increased risk of postpartum pre-diabetes or diabetes.

RESEARCH DESIGN AND METHODS—In this prospective cohort study, 487 women underwent 1) antepartum GDM screening by a glucose challenge test (GCT) and a diagnostic oral glucose tolerance test (OGTT) and 2) postpartum metabolic characterization by OGTT at 3 months after delivery. Four baseline glucose tolerance groups were defined on the basis of the antepartum GCT/OGTT: 1) GDM (n = 137); 2) gestational impaired glucose tolerance (GIGT) (n = 91); 3) abnormal GCT with normal glucose tolerance on an OGTT (abnormal GCT NGT) (n = 166); and 4) normal GCT with NGT on an OGTT (normal GCT NGT) (n = 93).

RESULTS—The prevalence of postpartum glucose intolerance (pre-diabetes or diabetes) increased across the groups from normal GCT NGT (3.2%) to abnormal GCT NGT (10.2%) to GIGT (16.5%) to GDM (32.8%) (Ptrend < 0.0001). On logistic regression analysis, all three categories of abnormal glucose homeostasis in pregnancy independently predicted postpartum glucose intolerance: abnormal GCT NGT odds ratio (OR) 3.6 (95% CI 1.01–12.9); GIGT OR 5.7 (1.6–21.1); and GDM OR 14.3 (4.2–49.1). Furthermore, both in pregnancy and at 3 months postpartum, insulin sensitivity (ISOGTT) and pancreatic β-cell function (insulinogenic index/homeostasis model assessment of insulin resistance) progressively decreased across the groups from normal GCT NGT to abnormal GCT NGT to GIGT to GDM (all Ptrend < 0.0001).

CONCLUSIONS—Any degree of abnormal glucose homeostasis in pregnancy independently predicts an increased risk of glucose intolerance postpartum.