bluuebunny/crossref_metadata_2025 huggingface dataset:
RANKL inhibition by osteoprotegerin prevents bone loss without affecting local or systemic inflammation parameters in two rat arthritis models: comparison with anti-TNFα or anti-IL-1 therapies
Authors: Stolina Marina , Schett Georg , Dwyer Denise , Vonderfecht Steven , Middleton Scot , Duryea Diane , Pacheco Efrain , Van Gwyneth , Bolon Brad , Feige Ulrich , Zack Debra , Kostenuik Paul
Published: December 2009

Introduction

Rat adjuvant-induced arthritis (AIA) and collagen-induced arthritis (CIA) feature bone loss and systemic increases in TNFα, IL-1β, and receptor activator of NF-κB ligand (RANKL). Anti-IL-1 or anti-TNFα therapies consistently reduce inflammation in these models, but systemic bone loss often persists. RANKL inhibition consistently prevents bone loss in both models without reducing joint inflammation. Effects of these therapies on systemic markers of bone turnover and inflammation have not been directly compared.

Methods

Lewis rats with established AIA or CIA were treated for 10 days (from day 4 post onset) with either PBS (Veh), TNFα inhibitor (pegsunercept), IL-1 inhibitor (anakinra), or RANKL inhibitor (osteoprotegerin (OPG)-Fc). Local inflammation was evaluated by monitoring hind paw swelling. Bone mineral density (BMD) of paws and lumbar vertebrae was assessed by dual X-ray absorptiometry. Markers and mediators of bone resorption (RANKL, tartrate-resistant acid phosphatase 5b (TRACP 5B)) and inflammation (prostaglandin E2 (PGE2), acute-phase protein alpha-1-acid glycoprotein (α1AGP), multiple cytokines) were measured in serum (day 14 post onset).

Results

Arthritis progression significantly increased paw swelling and ankle and vertebral BMD loss. Anti-TNFα reduced paw swelling in both models, and reduced ankle BMD loss in AIA rats. Anti-IL-1 decreased paw swelling in CIA rats, and reduced ankle BMD loss in both models. Anti-TNFα and anti-IL-1 failed to prevent vertebral BMD loss in either model. OPG-Fc reduced BMD loss in ankles and vertebrae in both models, but had no effect on paw swelling. Serum RANKL was elevated in AIA-Veh and CIA-Veh rats. While antiTNFα and anti-IL-1 partially normalized serum RANKL without any changes in serum TRACP 5B, OPG-Fc treatment reduced serum TRACP 5B by over 90% in both CIA and AIA rats. CIA-Veh and AIA-Veh rats had increased serum α1AGP, IL-1β, IL-8 and chemokine (C-C motif) ligand 2 (CCL2), and AIA-Veh rats also had significantly greater serum PGE2, TNFα and IL-17. Anti-TNFα reduced systemic α1AGP, CCL2 and PGE2 in AIA rats, while anti-IL-1 decreased systemic α1AGP, IL-8 and PGE2. In contrast, RANKL inhibition by OPG-Fc did not lessen systemic cytokine levels in either model.

Conclusions

Anti-TNFα or anti-IL-1 therapy inhibited parameters of local and systemic inflammation, and partially reduced local but not systemic bone loss in AIA and CIA rats. RANKL inhibition prevented local and systemic bone loss without significantly inhibiting local or systemic inflammatory parameters.
Serum levels of autoantibodies against C-reactive protein correlate with renal disease activity and response to therapy in lupus nephritis
Authors: Sjöwall Christopher , Zickert Agneta , Skogh Thomas , Wetterö Jonas , Gunnarsson Iva
Published: December 2009

Introduction

Serum levels of C-reactive protein (CRP) seldom reflect disease activity in systemic lupus erythematosus (SLE). We have previously shown that autoantibodies against neo-epitopes of CRP often occur in SLE, but that this does not explain the modest CRP response seen in flares. However, we have repeatedly found that anti-CRP levels parallel lupus disease activity, with highest levels in patients with renal involvement; thus, we aimed to study anti-CRP in a material of well-characterized lupus nephritis patients.

Methods

Thirty-eight patients with lupus nephritis were included. Treatment with corticosteroids combined with cyclophosphamide, mycophenolate mofetil or rituximab was started after baseline kidney biopsy. A second biopsy was taken after ≥ 6 months. Serum creatinine, cystatin C, complement, anti-dsDNA, anti-CRP and urinalysis were done on both occasions. Biopsies were evaluated regarding World Health Organisation (WHO) class and indices of activity and chronicity. Renal disease activity was estimated using the British Isles Lupus Assessment Group (BILAG) index.

Results

At baseline, 34/38 patients had renal BILAG-A; 4/38 had BILAG-B. Baseline biopsies showed WHO class III (n = 8), IV (n = 19), III to IV/V (n = 3) or V (n = 8) nephritis. Seventeen out of 38 patients were anti-CRP-positive at baseline, and six at follow-up. Overall, anti-CRP levels had dropped at follow-up (P < 0.0001) and anti-CRP levels correlated with renal BILAG (r = 0.29, P = 0.012). A positive anti-CRP test at baseline was superior to anti-dsDNA and C1q in predicting poor response to therapy as judged by renal BILAG. Baseline anti-CRP levels correlated with renal biopsy activity (r = 0.33, P = 0.045), but not with chronicity index. Anti-CRP levels were positively correlated with anti-dsDNA (fluorescence-enhanced immunoassay: r = 0.63, P = 0.0003; Crithidia luciliae immunofluorescence microscopy test: r = 0.44, P < 0.0001), and inversely with C3 (r = 0.35, P = 0.007) and C4 (r = 0.29, P = 0.02), but not with C1q (r = 0.14, P = 0.24). No associations with urinary components, creatinine, cystatin C or the glomerular filtration rate were found.

Conclusions

In the present study, we demonstrate a statistically significant correlation between anti-CRP levels and histopathological activity in lupus nephritis, whereas a baseline positive anti-CRP test predicted poor response to therapy. Our data also confirm previous findings of associations between anti-CRP and disease activity. This indicates that anti-CRP could be helpful to assess disease activity and response to therapy in SLE nephritis, and highlights the hypothesis of a pathogenetic role for anti-CRP antibodies in lupus nephritis.
Th1 and Th17 hypercytokinemia as early host response signature in severe pandemic influenza
Authors: Bermejo-Martin Jesus F , Ortiz de Lejarazu Raul , Pumarola Tomas , Rello Jordi , Almansa Raquel , Ramírez Paula , Martin-Loeches Ignacio , Varillas David , Gallegos Maria C , Serón Carlos , Micheloud Dariela , Gomez JoseManuel , Tenorio-Abreu Alberto , Ramos María J , Molina MLourdes , Huidobro Samantha , Sanchez Elia , Gordón Mónica , Fernández Victoria , del Castillo Alberto , Marcos MaÁngeles , Villanueva Beatriz , López CarlosJavier , Rodríguez-Domínguez Mario , Galan Juan-Carlos , Cantón Rafael , Lietor Aurora , Rojo Silvia , Eiros Jose M , Hinojosa Carmen , Gonzalez Isabel , Torner Nuria , Banner David , Leon Alberto , Cuesta Pablo , Rowe Thomas , Kelvin David J
Published: December 2009

Introduction

Human host immune response following infection with the new variant of A/H1N1 pandemic influenza virus (nvH1N1) is poorly understood. We utilize here systemic cytokine and antibody levels in evaluating differences in early immune response in both mild and severe patients infected with nvH1N1.

Methods

We profiled 29 cytokines and chemokines and evaluated the haemagglutination inhibition activity as quantitative and qualitative measurements of host immune responses in serum obtained during the first five days after symptoms onset, in two cohorts of nvH1N1 infected patients. Severe patients required hospitalization (n = 20), due to respiratory insufficiency (10 of them were admitted to the intensive care unit), while mild patients had exclusively flu-like symptoms (n = 15). A group of healthy donors was included as control (n = 15). Differences in levels of mediators between groups were assessed by using the non parametric U-Mann Whitney test. Association between variables was determined by calculating the Spearman correlation coefficient. Viral load was performed in serum by using real-time PCR targeting the neuraminidase gene.

Results

Increased levels of innate-immunity mediators (IP-10, MCP-1, MIP-1β), and the absence of anti-nvH1N1 antibodies, characterized the early response to nvH1N1 infection in both hospitalized and mild patients. High systemic levels of type-II interferon (IFN-γ) and also of a group of mediators involved in the development of T-helper 17 (IL-8, IL-9, IL-17, IL-6) and T-helper 1 (TNF-α, IL-15, IL-12p70) responses were exclusively found in hospitalized patients. IL-15, IL-12p70, IL-6 constituted a hallmark of critical illness in our study. A significant inverse association was found between IL-6, IL-8 and PaO2 in critical patients.

Conclusions

While infection with the nvH1N1 induces a typical innate response in both mild and severe patients, severe disease with respiratory involvement is characterized by early secretion of Th17 and Th1 cytokines usually associated with cell mediated immunity but also commonly linked to the pathogenesis of autoimmune/inflammatory diseases. The exact role of Th1 and Th17 mediators in the evolution of nvH1N1 mild and severe disease merits further investigation as to the detrimental or beneficial role these cytokines play in severe illness.
Pivotal Advance: Bifidobacteria and Gram-negative bacteria differentially influence immune responses in the proinflammatory milieu of celiac disease
Authors: De Palma G , Cinova J , Stepankova R , Tuckova L , Sanz Y
Published: December 2009

Immunomodulatory effects of intestinal bacteria under the immune (IFN-γ) and environmental triggers (gliadins) of celiac disease on peripheral blood mononuclear cells.

CD is a chronic inflammatory disorder of the small intestine that presents in genetically predisposed individuals following gluten consumption. In this study, the effects of Bifidobacterium (Bifidobacterium bifidum IATA-ES2 and Bifidobacterium longum ATCC15707) and Gram-negative bacteria (Bacteroides fragilis DSM2451, Escherichia coli CBL2, and Shigella CBD8 isolated from CD patients), alone and in the presence of CD triggers (gliadins and/or IFN-γ) on surface marker expression and cytokine production by PBMCs, were determined. These effects were also evaluated in cocultures of PBMCs and Caco-2 cells. The Gram-negative bacteria induced higher secretion of Th1-type proinflammatory cytokines (IL-12 and/or IFN-γ) than the Bifidobacterium strains. Shigella CBD8 and E. coli CBL2 up-regulated mainly HLA-DR and CD40 expression involved in Th1 activation, and Bifidobacterium strains up-regulated CD83 expression. Specific interactions among the studied bacteria, gliadins, and IFN-γ, which favored the CD immune features, were also detected. Therefore, intestinal bacteria could be additional factors that regulate the ability of monocytes recruited to the mucosa to respond to gliadins and IFN-γ in CD patients, influencing the course of the disease.
Estimation of primaries and near-offset reconstruction by sparse inversion: Marine data applications
Authors: van Groenestijn G. J. A. , Verschuur D. J.
Published: December 2009

Most wave-equation-based multiple removal algorithms are based on prediction and subtraction of multiples. Especially for shallow water, the prediction strongly relies on a correct interpolation of the missing near offsets. The subtraction of predicted multiples from the data can easily lead to the distortion of primaries if primaries and multiples overlap. Recently, a new approach for surface-related multiple removal was proposed: the estimation of primaries by sparse inversion (EPSI), which is based on a full waveform inversion approach. EPSI is based on the same primary-multiple model as surface-related multiple elimination (SRME) and does not require a subsurface model. In contrast to SRME, EPSI estimates the primaries as unknowns in a multidimensional inversion process rather than a subtraction process.The multidimensional primary impulse responses are parameterized by band-limited spikes, which are estimated such that they, along with their corresponding multiples, match the input data. An interesting aspect of the EPSI method is that it produces a residual, which is the part of the input data not explained by primaries and multiples. This residual can be analyzed and may provide useful information on the primary estimation process. Furthermore, it has been demonstrated that EPSI is also capable of reconstructing the missing near offsets from the multiples. The proposed method is applied to a field data set with moderate water depth, where it is demonstrated that the results are comparable with SRME. This data set is used to illustrate the residual. For a shallow-water field data set, it is shown that EPSI gives a better result than the standard SRME result caused by EPSI’s capability to reconstruct the missing near offsets.
The Bottleneck in the Cancer Biomarker Pipeline and Protein Quantification through Mass Spectrometry–Based Approaches: Current Strategies for Candidate Verification
Authors: Makawita Shalini , Diamandis Eleftherios P
Published: December 2009

Background: Although robust discovery-phase platforms have resulted in the generation of large numbers of candidate cancer biomarkers, a comparable system for subsequent quantitative assessment and verification of all candidates is lacking. Established immunoassays and available antibodies permit analysis of small subsets of candidates; however, the lack of commercially available reagents, coupled with high costs and lengthy production and purification times, have rendered the large majority of candidates untestable.

Content: Mass spectrometry (MS), and in particular multiple reaction monitoring (MRM)-MS, has emerged as an alternative technology to immunoassays for quantification of target proteins. Novel biomarkers are expected to be present in serum in the low (μg/L–ng/L) range, but analysis of complex serum or plasma digests by MS has yielded milligram per liter limits of detection at best. The coupling of prior sample purification strategies such as enrichment of target analytes, depletion of high-abundance proteins, and prefractionation, has enabled reliable penetration into the low microgram per liter range. This review highlights prospects for candidate verification through MS-based methods. We first outline the biomarker discovery pipeline and its existing bottleneck; we then discuss various MRM-based strategies for targeted protein quantification, the applicability of such methods for candidate verification, and points of concern.

Summary: Although it is unlikely that MS-based protein quantification will replace immunoassays in the near future, with the expected improvements in limits of detection and specificity in instrumentation, MRM-based approaches show great promise for alleviating the existing bottleneck to discovery.
Quantification of Serum 1–84 Parathyroid Hormone in Patients with Hyperparathyroidism by Immunocapture In Situ Digestion Liquid Chromatography–Tandem Mass Spectrometry
Authors: Kumar Vivek , Barnidge David R , Chen Li-Sheng , Twentyman Jolaine M , Cradic Kendall W , Grebe Stefan K , Singh Ravinder J
Published: December 2009

Background: Immunoassays specific for 1–84 parathyroid hormone (PTH) reportedly reflect the bioactivity of PTH; however, PTH immunoassays can be susceptible to interference by cross-reacting PTH fragments. In addition, these assays currently lack standardization. A methodology using immunocapture purification with liquid chromatography–tandem mass spectrometry (LC-MS/MS) detection, along with a stable isotope–labeled internal standard, may help address these issues.

Methods: We isolated 1–84 PTH from 1 mL serum by immunocapture on a 6.5-mm polystyrene bead. The immobilized PTH was digested in situ and analyzed by LC-MS/MS. For quantification, we used the selected reaction monitoring response from the N-terminal tryptic peptide 1–13 PTH (1SVSEIQLMHNLGK13).

Results: The linear range of the assay was 39.1–4560 ng/L, and the limit of detection and limit of quantification were 14.5 ng/L and 39.1 ng/L, respectively. The intraassay CVs ranged from 6% to 11%, and the interassay CVs ranged from 7% to 17%. Interference by PTH fragments 1–44 PTH, 7–84 PTH, 43–68 PTH, 52–84 PTH, 64–84 PTH, and PTH-related protein (PTHrP) was ≤1% to ≤0.001%. Method comparison of LC-MS/MS vs the Roche Cobas® immunoassay yielded Deming fit of LC-MS/MS = 1.01x immunoassay – 13.21. The mean bias by Bland–Altman plot was −9.4%.

Conclusions: In patients with hyperparathyroidism, the immunocapture in situ digestion LC-MS/MS method can provide accurate and precise PTH results compared with immunoassay.
Prevalence of Weight Concerns and Obesity Among Smokers Calling a Quitline
Authors: Bush Terry , Levine Michele D. , Deprey Mona , Cerutti Barbara , Zbikowski Susan M. , McAfee Tim , Mahoney Lisa , Beebe Laura
Published: December 2009

Background: Cessation-related weight gain and weight concerns are common among smokers and have a negative impact on quitting. Obese smokers tend to gain more than the average amount of weight and also have lower quit rates. This article describes the prevalence of obesity and weight concerns among smokers calling a state quitline in the United States. Results: Among 3972 smokers using a state quitline, 33.3% were obese, 30.2% overweight, 33.3% normal weight and 3.2% under-weight; a total of 60.6% were concerned about cessation-related weight gain. Compared with non-obese callers, obese callers were more likely to be female, Hispanic, non-White and heavier smokers. Conclusions: This is the first study to report data on body weight and weight concerns of smokers calling a national quitline. Given the lower quit rates among obese and weight-concerned smokers, and the burden of smoking and obesity, there is an opportunity to develop new treatment approaches for this at-risk population.
Understanding Former Smokers in Canada: Examining Who They are and When, Why and How They Quit
Authors: Ismailov Rovshan M. , Leatherdale Scott T.
Published: December 2009

Objectives: Although the benefits of smoking cessation are well established, long-term abstinence from cigarettes is difficult for many smokers to achieve. We aimed to examine quit attempts, years since quitting and factors associated with long-term abstinence among former smokers.Methods: Data were from the 2006 Canadian Tobacco Use Monitoring Survey. Descriptive analyses were performed and logistic regression models were used to examine factors associated with long-term abstinence (more than 5 years) among former smokers.Results: In 2006, over one in four Canadians (27.1%,n= 7,200,000) aged 15 and older was a former smoker. The prevalence of former smoking was higher among men (30.9%) in comparison to women (23.4%). Former smokers who quit in the past 3 years or earlier were more likely to be older as well as have children younger than 15 in the household. Logistic regression analyses revealed that older age was a significant predictor of long-term abstinence from smoking.Conclusion: Our findings suggest that there are modifiable characteristics associated with long-term smoking abstinence that could be addressed by relapse prevention programming. Longitudinal data are warranted to further clarify the relationship between certain characteristic of former smokers and the duration of abstinence.
Sensitivity Analysis of the Efficacy of Varenicline in Smoking Cessation With a Special Reference to Study Dropouts
Authors: Oshima Akira , Ito Yuri , Nomura Hideki
Published: December 2009

We conducted a sensitivity analysis under four scenarios using data from three Asian studies conducted with low dropout rates to evaluate the efficacy of varenicline in smoking cessation within a scenario where dropouts from the study are dealt with in a manner as unfavourable as possible to varenicline. Pooled odds ratio of continuous abstinence at week 24 was 1.55 (95% confidence interval: 1.03–2.35, random-effect model) under the scenario where dropouts from the varenicline group were dealt with as smokers and those from the placebo group as successful quitters. From the present study, the efficacy of varenicline has been firmly established in the Asian population.
Inhibition of oocyte growth factors in vivo modulates ovarian folliculogenesis in neonatal and immature mice
Authors: Myllymaa Samu , Pasternack Arja , Mottershead David G , Poutanen Matti , Pulkki Minna M , Pelliniemi Lauri J , Ritvos Olli , Laitinen Mika P E
Published: December 2009

Growth differentiation factor-9 (GDF9) and bone morphogenetic protein-15 (BMP15) are among the key regulators transmitting the signaling between the oocyte and the surrounding granulosa cells. Previously, it has been shown that a recombinant BMP type II receptor ectodomain–Fc fusion protein (BMPR2ecd–Fc) is able to inhibit the actions of GDF9 and BMP15in vitro. Here, we have produced bioactive BMPR2ecd–Fc, which was injected i.p. into neonatal mice. Early folliculogenesis was first studied by injecting mice five times with various doses of BMPR2ecd–Fc during the postnatal days 4–12. Folliculogenesis was affected dose dependently, as evidenced by a decreased mitogenesis of granulosa cells of the growing follicles. Furthermore, we also noticed a decrease in the number of secondary and tertiary follicles as well as an increase in the oocyte size. Electron microscopic analysis revealed that the ultrastructure of the granulosa cells of the primary follicles was not affected by the BMPR2ecd–Fc treatment. A second study was conducted to investigate whether a longer treatment with 12 injections during postnatal days 4–28 would inhibit folliculogenesis. Similar effects were observed in the two studies on the early follicular developmental stages. However, in the long-term study, later stages of folliculogenesis were not blocked but rather increased numbers of antral follicles, preovulatory follicles, and corpora lutea were found. We conclude that BMPR2ecd–Fc is a potent modulator of ovarian folliculogenesisin vivo, and thus, is a valuable tool for studying the physiology and downstream effects of oocyte-derived growth factorsin vivo.
The Case for Chemotherapy Only for Localized Hodgkin Lymphoma
Authors: Straus David J.
Published: December 2009

Although radiation therapy (RT) alone, and more recently in combination with chemotherapy, has been the cornerstone of curative treatment for early-stage Hodgkin lymphoma for >40 years, the late toxicities of this treatment are increasingly being recognized as causes of significant late morbidity and mortality. In recent years, the focus of treatment of early-stage Hodgkin lymphoma has been reductions in the doses and fields of RT and attempts to reduce the amount and the toxicity of chemotherapy. Another approach has been to treat with chemotherapy alone and to eliminate RT entirely unless it is absolutely necessary. This review summarizes the accumulating information on the late side effects of treatment of Hodgkin lymphoma, the results of trials with chemotherapy only, attempts to reduce the toxicity of chemotherapy, and the new role of positron emission tomography in treatment planning.
When “Flawed” Translates into “Flood”: The Unproven Association Between Cancer Incidence and Glargine Insulin Therapy
Authors: Miguel-Yanes Jose M. , Meigs James B.
Published: December 2009

The authors comment on the unproven association between cancer risk and glargine insulin therapy.
Dehydroepiandrosterone-induced proliferation of prostatic epithelial cell is mediated by NFKB via PI3K/AKT signaling pathway
Authors: Sun Hong-Zhi , Yang Tong-Wei , Zang Wei-Jin , Wu Shu-Fang
Published: December 2009

Dehydroepiandrosterone (DHEA) is an endogenous steroid that is metabolized to androgens and/or estrogens in the human prostate. DHEA levels decline with age, and use of DHEA supplements to retard the aging process is of unproved effectiveness and safety. In this study, rat ventral prostatic epithelial cells were used to determine whether DHEA-modulated proliferation and prostate-specific antigen (PSA listed as KLKB1 in the MGI Database) production were mediated via the androgen receptor (AR) and its potential mechanism. We demonstrated that proliferation of prostatic epithelial cells and increase of PSA expression induced by DHEA were neutralized by Casodex or Ar siRNA, two specific AR blockers. DHEA stimulated Nfkb DNA binding activity, with this effect being blunted by Casodex or Ar siRNA. Moreover, the inhibition of the phosphatidylinositol 3-kinase (PI3K)/AKT nullified the effects of DHEA on NFKB activation. These findings suggested that DHEA stimulated normal prostatic epithelial cell proliferation, and AR is involved in DHEA-induced PSA expression in normal prostatic epithelial cells. This stimulation effect induced by DHEA is mediated by the activation of NFKB via PI3K/AKT pathway.
Geometric Asymptotic Approximation of Value Functions
Authors: Anderson Axel
Published: December 2009

This paper characterizes the behavior of value functions in dynamic stochastic discounted programming models near fixed points of the state space. When the second derivative of the flow payoff function is bounded, the value function is proportional to a linear function plus geometric term. A specific formula for the exponent of this geometric term is provided. This exponent continuously falls in the rate of patience.If the state variable is a martingale, the second derivative of the value function is unbounded. If the state variable is instead a strict local submartingale, then the same holds for the first derivative of the value function. Thus, the proposed approximation is more accurate than Taylor series approximation.The approximation result is used to characterize locally optimal policies in several fundamental economic problems.
Calculating Pulmonary-Mode-Lethality Risk Avoidance Associated with Radionuclide Decorporation Countermeasures Related to a Radiological Terrorism Incident
Authors: Scott Bobby R.
Published: December 2009

Planning for and managing radiological terrorism incidents that involve the release of radionuclides from a dirty bomb requires considering the potential lifesaving impact of protective radionuclide decorporation countermeasures (e.g., lung lavage). Lung lavage therapy could prevent deaths via the pulmonary mode (which involves radiation pneumonitis and fibrosis) by reducing the radiation dose to the lung from inhaled radionuclides. The risk avoidance ( RAV) assessment framework introduced in a related paper is used to evaluate the pulmonary-lethality-mode RAV due to lung lavage and the associated risk avoidance proportion ( RAP) for hypothetical inhalation-exposure scenarios. The lethality RAV is a measure (on a scale from 0 to 1) of the actual risk reduction associated with the applied protective countermeasures. The lethality RAP is the lethality RAV divided by the lethality risk when no protective countermeasures are employed and is a useful measure of the efficacy of the countermeasures applied. Examples of pulmonary-mode lethality RAV and RAP calculations are presented for hypothetical scenarios involving lung lavage to remove beta and/or gamma-emitting radionuclides that are inhaled in highly insoluble forms. The approach presented could be used to develop optimal schemes for applying lung lavage therapy following a terrorist incident involving a dirty bomb.
Low-Dose Cancer Risk Modeling Must Recognize Up-Regulation of Protection
Authors: Feinendegen Ludwig E. , Pollycove Myron , Neumann Ronald D.
Published: December 2009

Ionizing radiation primarily perturbs the basic molecular level proportional to dose, with potential damage propagation to higher levels: cells, tissues, organs, and whole body. There are three types of defenses against damage propagation. These operate deterministically and below a certain impact threshold there is no propagation. Physical-static defenses precede metabolic-dynamic defenses acting immediately: scavenging of toxins; - molecular repair, especially of DNA; - removal of damaged cells either by apoptosis, necrosis, phagocytosis, cell differentiation-senescence, or by immune responses, - followed by replacement of lost elements. Another metabolic-dynamic defense arises delayed by up-regulating immediately operating defense mechanisms. Some of these adaptive protections may last beyond a year and all create temporary protection against renewed potentially toxic impacts also from non-radiogenic endogenous sources. Adaptive protections have a maximum after single tissue absorbed doses around 100 to 200 mSv and disappear with higher doses. Low dose rates initiate maximum protection likely at lower cell doses delivered repetitively at certain time intervals. Adaptive protection preventing only about 2 – 3 % of endogenous life-time cancer risk would fully balance a calculated induced cancer risk at about 100 mSv, in agreement with epidemiological data and concordant with an hormetic effect. Low-dose-risk modeling must recognize up-regulation of protection.
Hormesis can and Does Work in Humans
Authors: Rattan Suresh I. S. , Demirovic Dino
Published: December 2009

If we accept the validity of the general concept of physiological hormesis as being the phenomenon of achieving health beneficial effects by exposure to mild stress, then hormesis is being applied already and successfully to humans. The evidence for this is the well-demonstrated health benefits of regular and moderate exercise. Mild stress-induced activation of one or more intracellular pathways of stress response are central to this. Experimental studies performed on human cells in culture exposed to mild heat shock and other stresses provide biochemical and molecular evidence in support of the application of hormesis to human systems. Although several issues remain to be resolved by more research with respect to the extent and duration of hormetic exposure, making use of the cellular stress response pathways can facilitate discovering novel hormetins for human applications.
A Central Role of RLIP76 in Regulation of Glycemic Control
Authors: Awasthi Sanjay , Singhal Sharad S. , Yadav Sushma , Singhal Jyotsana , Vatsyayan Rit , Zajac Ewa , Luchowski Rafal , Borvak Jozef , Gryczynski Karol , Awasthi Yogesh C.
Published: December 2009

OBJECTIVE

Pathology associated with oxidative stress frequently results in insulin resistance. Glutathione (GSH) and GSH-linked metabolism is a primary defense against oxidative stress. Electrophilic lipid alkenals, such as 4-hydroxy-t-2-nonenal (4HNE), generated during oxidative stress are metabolized primarily to glutathione electrophile (GS-E) conjugates. Recent studies show that RLIP76 is the primary GS-E conjugate transporter in cells, and a regulator of oxidative-stress response. Because RLIP76−/− mice are hypoglycemic, we studied the role of RLIP76 in insulin resistance.

RESEARCH DESIGN AND METHODS

Blood glucose, insulin, lipid measurements, and hyperinsulinemic-euglycemic and hyperglycemic clamp experiments were performed in RLIP76+/+ and RLIP76−/− C57B mice, using Institutional Animal Care and Use Committee–approved protocols. Time-resolved three-dimensional confocal fluorescence microscopy was used to study insulin endocytosis.

RESULTS

The plasma insulin/glucose ratio was ordered RLIP76−/− < RLIP76+/− < RLIP76+/+; administration of purified RLIP76 in proteoliposomes to RLIP76+/+ animals further increased this ratio. RLIP76 was induced by oxidative or hyperglycemic stress; the concomitant increase in insulin endocytosis was completely abrogated by inhibiting the transport activity of RLIP76. Hydrocortisone could transiently correct hypoglycemia in RLIP76−/− animals, despite inhibited activity of key glucocorticoid-regulated hepatic gluconeogenic enzymes, phosphoenolpyruvate carboxykinase, glucose-6-phosphatase, and fructose 1,6-bisphosphatase, in RLIP76−/−.

CONCLUSIONS

The GS-E conjugate transport activity of RLIP76 mediates insulin resistance by enhancing the rate of clathrin-dependent endocytosis of insulin. Because RLIP76 is induced by oxidative stress, it could play a role in insulin resistance seen in pathological conditions characterized by increased oxidative stress.
Insulin Gene Mutations Resulting in Early-Onset Diabetes: Marked Differences in Clinical Presentation, Metabolic Status, and Pathogenic Effect Through Endoplasmic Reticulum Retention
Authors: Meur Gargi , Simon Albane , Harun Nasret , Virally Marie , Dechaume Aurélie , Bonnefond Amélie , Fetita Sabrina , Tarasov Andrei I. , Guillausseau Pierre-Jean , Boesgaard Trine Welløv , Pedersen Oluf , Hansen Torben , Polak Michel , Gautier Jean-François , Froguel Philippe , Rutter Guy A. , Vaxillaire Martine
Published: December 2009

OBJECTIVE

Heterozygous mutations in the human preproinsulin (INS) gene are a cause of nonsyndromic neonatal or early-infancy diabetes. Here, we sought to identify INS mutations associated with maturity-onset diabetes of the young (MODY) or nonautoimmune diabetes in mid-adult life, and to explore the molecular mechanisms involved.

RESEARCH DESIGN AND METHODS

The INS gene was sequenced in 16 French probands with unexplained MODY, 95 patients with nonautoimmune early-onset diabetes (diagnosed at <35 years) and 292 normoglycemic control subjects of French origin. Three identified insulin mutants were generated by site-directed mutagenesis of cDNA encoding a preproinsulin–green fluorescent protein (GFP) (C-peptide) chimera. Intracellular targeting was assessed in clonal β-cells by immunocytochemistry and proinsulin secretion, by radioimmunoassay. Spliced XBP1 and C/EBP homologous protein were quantitated by real-time PCR.

RESULTS

A novel coding mutation, L30M, potentially affecting insulin multimerization, was identified in five diabetic individuals (diabetes onset 17–36 years) in a single family. L30M preproinsulin-GFP fluorescence largely associated with the endoplasmic reticulum (ER) in MIN6 β-cells, and ER exit was inhibited by ∼50%. Two additional mutants, R55C (at the B/C junction) and R6H (in the signal peptide), were normally targeted to secretory granules, but nonetheless caused substantial ER stress.

CONCLUSIONS

We describe three INS mutations cosegregating with early-onset diabetes whose clinical presentation is compatible with MODY. These led to the production of (pre)proinsulin molecules with markedly different trafficking properties and effects on ER stress, demonstrating a range of molecular defects in the β-cell.
Development and Validation of a Questionnaire to Assess Carbohydrate and Insulin-Dosing Knowledge in Youth With Type 1 Diabetes
Authors: Koontz Michaela B. , Cuttler Leona , Palmert Mark R. , O'Riordan MaryAnn , Borawski Elaine A. , McConnell Judy , Kern Elizabeth O.
Published: December 2009

OBJECTIVE

The American Diabetes Association advocates insulin regimens for youth with type 1 diabetes that involve adjusting insulin dose based on carbohydrate intake and blood glucose level. Implementing these regimens requires knowledge about carbohydrate content of foods and subsequent calculations of insulin dose, skills that may be difficult to gauge in practice. Therefore, we sought to develop and validate a questionnaire, the PedCarbQuiz (PCQ), to assess carbohydrate and insulin-dosing knowledge in youth with type 1 diabetes.

RESEARCH DESIGN AND METHODS

After development by an expert panel, the PCQ was administered to 75 youth with type 1 diabetes or their parents. Reliability was assessed by Cronbach α and split-half testing. To assess validity, scores were correlated with A1C, expert assessments, parent educational level, and complexity of insulin regimen.

RESULTS

PCQ mean score was 87 ± 9.7% (range 42–98%). Cronbach α was 0.88, and correlation of split halves was 0.59 (P < 0.0001). Higher PCQ scores correlated significantly with lower A1C (r = −0.29, P = 0.01) and expert assessments (r = 0.56, P < 0.001). Scores were significantly higher in parents with college degrees than in those without (P = 0.01) and in participants with more complex insulin regimens (P = 0.003).

CONCLUSIONS

The PCQ is a novel, easily administered instrument to assess knowledge about carbohydrates and insulin dosing calculations. Initial analyses support the reliability and validity of the PCQ.
Racial and Ethnic Differences in an Estimated Measure of Insulin Resistance Among Individuals With Type 1 Diabetes
Authors: Danielson Kirstie K. , Drum Melinda L. , Estrada Carmela L. , Lipton Rebecca B.
Published: December 2009

OBJECTIVE

Insulin resistance is greater in racial/ethnic minorities than in non-Hispanic whites (NHWs) for those with and without type 2 diabetes. Because previous research on insulin resistance in type 1 diabetes was limited to NHWs, racial/ethnic variation in an estimated measure of insulin resistance in type 1 diabetes was determined.

RESEARCH DESIGN AND METHODS

The sample included 79 individuals with type 1 diabetes diagnosed at age <18 years (32.9% NHWs, 46.8% non-Hispanic black [NHB], 7.6% other/mixed, and 12.7% Hispanic) and their families. Estimated glucose disposal rate (eGDR) (milligrams per kilogram per minute; a lower eGDR indicates greater insulin resistance) was calculated using A1C, waist circumference, and hypertension status.

RESULTS

Mean current age was 13.5 years (range 3.2–32.5) and diabetes duration was 5.7 years (0.1–19.9). eGDR was inversely associated with age. Compared with that in NHWs, age-adjusted eGDR was significantly lower among nonwhites (NHB, other/mixed, and Hispanic: Δ = −1.83, P = 0.0006). Age-adjusted eGDR was negatively associated with body fat, triglycerides, urinary albumin/creatinine, acanthosis nigricans, parental obesity, and parental insulin resistance and positively related to HDL and sex hormone–binding globulin. In multivariable analysis, lower eGDR was significantly associated with older age, nonwhite race/ethnicity, acanthosis, and lower HDL.

CONCLUSIONS

Minorities with type 1 diabetes are significantly more insulin resistant, as measured by eGDR, than NHWs. Exploring potential mechanisms, including disparities in care and/or physiological variation, may contribute to preventing racial/ethnic differences in insulin resistance–associated outcomes.
Relationship Styles and Mortality in Patients With Diabetes
Authors: Ciechanowski Paul , Russo Joan , Katon Wayne J. , Lin Elizabeth H.B. , Ludman Evette , Heckbert Susan , Von Korff Michael , Williams Lisa H. , Young Bessie A.
Published: December 2009

OBJECTIVE

Prior research has shown that less social support is associated with increased mortality in individuals with chronic illnesses. We set out to determine whether lower propensity to seek support as indicated by relationship style, based on attachment theory, is associated with mortality in patients with diabetes.

RESEARCH DESIGN AND METHODS

A total of 3,535 nondepressed adult patients with type 1 and type 2 diabetes enrolled in a health maintenance organization in Washington State were surveyed at baseline and followed for 5 years. Relationship style was assessed at baseline. Patients with a greater propensity to seek support were classified as having an interactive relationship style and those less inclined to seek support as having an independent relationship style. We collected Washington State mortality data and used Cox proportional hazards models to estimate relative risk (RR) of death for relationship style groups.

RESULTS

The rate of death in the independent and interactive relationship style groups was 39 and 29 per 1,000 individuals, respectively. Unadjusted RR of death was 1.33 (95% CI 1.12–1.58), indicating an increased risk of death among individuals with an independent relationship style. After adjustment for demographic and clinical covariates, those with an independent relationship style still had a greater risk of death compared with those with an interactive relationship style (hazard ratio 1.20 [95% CI 1.01–1.43]).

CONCLUSIONS

In a large sample of adult patients with diabetes, a lower propensity to reach out to others is associated with higher mortality over 5 years. Further research is needed to examine possible mechanisms for this relationship and to develop appropriate interventions.
Performance of an A1C and Fasting Capillary Blood Glucose Test for Screening Newly Diagnosed Diabetes and Pre-Diabetes Defined by an Oral Glucose Tolerance Test in Qingdao, China
Authors: Zhou Xianghai , Pang Zengchang , Gao Weiguo , Wang Shaojie , Zhang Lei , Ning Feng , Qiao Qing
Published: December 2009

OBJECTIVE

The study's goal was to evaluate the performance of A1C and fasting capillary blood glucose (FCG) tests as mass screening tools for diabetes and pre-diabetes, as determined by the standard oral glucose tolerance test (OGTT).

RESEARCH DESIGN AND METHODS

Data from 2,332 individuals aged 35–74 years who participated in a population-based cross-sectional diabetes survey in Qingdao, China, were analyzed. A 2-h 75-g OGTT was used to diagnose diabetes. The performance of A1C and FCG was evaluated against the results of the OGTTs by using receiver operating characteristic curve (ROC) analysis.

RESULTS

The prevalence of newly diagnosed diabetes and pre-diabetes (impaired fasting glucose and/or impaired glucose tolerance) was 11.9 and 29.5%, respectively. For subjects with newly diagnosed diabetes, the area under the ROC curve was 0.67 for A1C and 0.77 for FCG (P < 0.01) in men and 0.67 and 0.75 (P < 0.01) in women, whereas for pre-diabetes, these values were 0.47 and 0.64 (P < 0.001) in men and 0.51 and 0.65 (P < 0.001) in women. At the optimal A1C cutoff point of ≥5.6% for newly diagnosed diabetes, sensitivities (specificities) were 64.4% (61.6%) for men and 62.3% (63.3%) for women.

CONCLUSIONS

As a screening tool for newly diagnosed diabetes and pre-diabetes, the FCG measurement performed better than A1C in this general Chinese population.
Hypoglycemia in Type 1 Diabetic Pregnancy
Authors: Heller Simon , Damm Peter , Mersebach Henriette , Skjøth Trine Vang , Kaaja Risto , Hod Moshe , Durán-García Santiago , McCance David , Mathiesen Elisabeth R.
Published: December 2009

OBJECTIVE

A recent randomized trial compared prandial insulin aspart (IAsp) with human insulin in type 1 diabetic pregnancy. The aim of this exploratory analysis was to investigate the incidence of severe hypoglycemia during pregnancy and compare women enrolled preconception with women enrolled during early pregnancy.

RESEARCH DESIGN AND METHODS

IAsp administered immediately before each meal was compared with human insulin administered 30 min before each meal in 99 subjects (44 to IAsp and 55 to human insulin) randomly assigned preconception and in 223 subjects (113 for IAsp and 110 for human insulin) randomly assigned in early pregnancy (<10 weeks). NPH insulin was the basal insulin. Severe hypoglycemia (requiring third-party assistance) was recorded prospectively preconception (where possible), during pregnancy, and postpartum. Relative risk (RR) of severe hypoglycemia was evaluated with a gamma frailty model.

RESULTS

Of the patients, 23% experienced severe hypoglycemia during pregnancy with the peak incidence in early pregnancy. In the first half of pregnancy, the RR of severe hypoglycemia in women randomly assigned in early pregnancy/preconception was 1.70 (95% CI 0.91–3.18, P = 0.097); the RR in the second half of pregnancy was 1.35 (0.38–4.77, P = 0.640). In women randomly assigned preconception, severe hypoglycemia rates occurring before and during the first and second halves of pregnancy and postpartum for IAsp versus human insulin were 0.9 versus 2.4, 0.9 versus 2.4, 0.3 versus 1.2, and 0.2 versus 2.2 episodes per patient per year, respectively (NS).

CONCLUSIONS

These data suggest that initiation of insulin analog treatment preconception rather than during early pregnancy may result in a lower risk of severe hypoglycemia in women with type 1 diabetes.
First-Trimester Follistatin-Like-3 Levels in Pregnancies Complicated by Subsequent Gestational Diabetes Mellitus
Authors: Thadhani Ravi , Powe Camille E. , Tjoa May Lee , Khankin Eliyahu , Ye Jun , Ecker Jeffrey , Schneyer Alan , Karumanchi S. Ananth
Published: December 2009

OBJECTIVE

To determine whether maternal levels of follistatin-like-3 (FSTL3), an inhibitor of activin and myostatin involved in glucose homeostasis, are altered in the first trimester of pregnancies complicated by subsequent gestational diabetes mellitus (GDM).

RESEARCH DESIGN AND METHODS

This was a nested case-control study of subjects enrolled in a prospective cohort of pregnant women with and without GDM (≥2 abnormal values on a 100-g glucose tolerance test at ∼28 weeks of gestation). We measured FSTL3 levels in serum collected during the first trimester of pregnancy. Logistic regression analyses were used to determine the risk of GDM.

RESULTS

Women who developed GDM (n = 37) had lower first-trimester serum levels of FSTL3 compared with women who did not (n = 127) (median 10,789 [interquartile range 7,013–18,939] vs. 30,670 [18,370–55,484] pg/ml, P < 0.001). When subjects were divided into tertiles based on FSTL3 levels, women with the lowest levels demonstrated a marked increase in risk for developing GDM in univariate (odds ratio 11.2 [95% CI 3.6–35.3]) and multivariate (14.0 [4.1–47.9]) analyses. There was a significant negative correlation between first-trimester FSTL3 levels and ∼28-week nonfasting glucose levels (r = −0.30, P < 0.001).

CONCLUSIONS

First-trimester FSTL3 levels are associated with glucose intolerance and GDM later in pregnancy.
Central elements in pseudoeffect algebras
Authors: Xie Yongjian , Li Yongming
Published: December 2009

We introduce the definition of pseudoorthoalgebras and discuss some relationships between orthomodular lattices and pseudoorthoalgebras. Then we study the conditions that a pseudoeffect algebra is isomorphic to an “internal direct product” of ideals generated by orthogonal principal elements. At last, we give some characterizations of central elements in pseudoeffect algebras.
(Pre-)coxeter algebras and related topics
Authors: Kim Chang , Kim Hee
Published: December 2009

In this paper we discuss some relations between (pre-)Coxeter algebras and its related topics, and obtain some equivalent conditions.
On extension theorems for M-measures in l-groups
Authors: Boccuto Antonio , Riečan Beloslav
Published: December 2009

Some extension theorems for l-group-valued M-measures are proved.
Application of fractional calculus operators for a new class of univalent functions with negative coefficients defined by Hohlov operator
Authors: Atshan Waggas
Published: December 2009

In this paper, we introduce a new class W(a, b, c, γ, β) which consists of analytic and univalent functions with negative coefficients in the unit disc defined by Hohlov operator, we obtain distortion theorem using fractional calculus techniques for this class. Also coefficient inequalities and some results for this class are obtained.
Optimal control of a coefficient in modification Navier-Stokes equations
Authors: Bilić Nataša
Published: December 2009

This paper deals with the optimal control of a coefficient in the modification of Navier-Stokes equations. Namely, the motion of the viscous incompressible fluid for a small gradient of velocity is described by Navier-Stokes equations where the coefficient of the kinematic viscosity ν is the positive constant (ν
0). For a greater gradient of velocity the coefficient of kinematic viscosity is a positive function of the gradient of velocity, that is ν (|∇u|). In our case ν (|∇u|) = ν
0 + ν
1
a (|∇u|) where ν
0, ν
1 ∈ ℝ+. The function a is positive and monotone and it is taken as a control variable. The existence of a solution of the optimal control problem is proved. Further, the approximation of the control problem by the finite-dimensional control problem is performed. The proof of the existence of a solution of that aproximate problem has been brought into light. Finally, the connection between the solution of the control problem and the solution of the approximate control problem is established.
Translatable radii of an operator in the direction of another operator II
Authors: Paul Kallol
Published: December 2009

One of the couple of translatable radii of an operator in the direction of another operator introduced in earlier work [PAUL, K.: Translatable radii of an operator in the direction of another operator, Scientae Mathematicae 2 (1999), 119–122] is studied in details. A necessary and sufficient condition for a unit vector f to be a stationary vector of the generalized eigenvalue problem Tf = λAf is obtained. Finally a theorem of Williams ([WILLIAMS, J. P.: Finite operators, Proc. Amer. Math. Soc. 26 (1970), 129–136]) is generalized to obtain a translatable radius of an operator in the direction of another operator.