bluuebunny/crossref_metadata_2025 huggingface dataset:
Revisiting immunosurveillance and immunostimulation: Implications for cancer immunotherapy
Authors: Ichim Christine V
Published: February 2005

Experimental and clinical experience demonstrates that the resolution of a pathogenic challenge depends not only on the presence or absence of an immune reaction, but also on the initiation of the proper type of immune reaction. The initiation of a non-protective type of immune reaction will not only result in a lack of protection, but may also exacerbate the underlying condition. For example, in cancer, constituents of the immune system have been shown to augment tumor proliferation, angiogenesis, and metastases. This review discusses the duality of the role of the immune system in cancer, from the theories of immunosurveillance and immunostimulation to current studies, which illustrate that the immune system has both a protective role and a tumor-promoting role in neoplasia. The potential of using chemotherapy to inhibit a tumor-promoting immune reaction is also discussed.
In vitro bioassay as a predictor of in vivo response
Authors: Barnard Ross , Gurevich Konstantin G
Published: February 2005

Background

There is a substantial discrepancy between in vitro and in vivo experiments. The purpose of the present work was development of a theoretical framework to enable improved prediction of in vivo response from in vitro bioassay results.

Results

For dose-response curve reaches a plateau in vitro we demonstrated that the in vivo response has only one maximum. For biphasic patterns of biological response in vitro both the bimodal and biphasic in vivo responses might be observed.

Conclusion

As the main result of this work we have demonstrated that in vivo responses might be predicted from dose-effect curves measured in vitro.
HIV-1 Tat, apoptosis and the mitochondria: a tubulin link?
Authors: Giacca Mauro
Published: February 2005

The Tat protein of HIV-1 is a powerful activator of viral gene expression. Besides this essential function at the HIV-1 promoter, the protein also exerts a remarkable number of other biological activities, among which the induction of cellular apoptosis. Two papers now published in Retrovirology provide possible molecular mechanisms for the pro-apoptotic effect of Tat, which involve the cell's microtubular network and the mitochondrial pathway of apoptosis.
Levels of gastrin-releasing peptide and substance P in synovial fluid and serum correlate with levels of cytokines in rheumatoid arthritis
Authors: Grimsholm Ola , Rantapää-Dahlqvist Solbritt , Forsgren Sture
Published: February 2005

It is well known that cytokines are highly involved in the disease process of rheumatoid arthritis (RA). Recently, targeting of neuropeptides has been suggested to have potential therapeutic effects in RA. The aim of this study was to investigate possible interrelations between five neuropeptides (bombesin/gastrin-releasing peptide (BN/GRP), substance P (SP), vasoactive intestinal peptide, calcitonin-gene-related peptide, and neuropeptide Y) and the three cytokines tumour necrosis factor (TNF)-α, IL-6, and monocyte chemoattractant protein-1 in synovial fluid of patients with RA. We also investigated possible interrelations between these neuropeptides and soluble TNF receptor 1 in serum from RA patients. Synovial fluid and sera were collected and assayed with ELISA or RIA. The most interesting findings were correlations between BN/GRP and SP and the cytokines. Thus, in synovial fluid, the concentrations of BN/GRP and SP grouped together with IL-6, and SP also grouped together with TNF-α and monocyte chemoattractant protein-1. BN/GRP and SP concentrations in synovial fluid also grouped together with the erythrocyte sedimentation rate. In the sera, BN/GRP concentrations and soluble TNF receptor 1 concentrations were correlated. These results are of interest because blocking of SP effects has long been discussed in relation to RA treatment and because BN/GRP is known to have trophic and growth-promoting effects and to play a role in inflammation and wound healing. Furthermore, the observations strengthen a suggestion that combination treatment with agents interfering with neuropeptides and cytokines would be efficacious in the treatment of RA. In conclusion, BN/GRP and SP are involved together with cytokines in the neuroimmunomodulation that occurs in the arthritic joint.
Serum cystatin C concentration as a marker of acute renal dysfunction in critically ill patients
Authors: Villa Patricia , Jiménez Manuel , Soriano Maria-Cruz , Manzanares Jesus , Casasnovas Pilar
Published: February 2005

Introduction

In critically ill patients sudden changes in glomerular filtration rate (GFR) are not instantly followed by parallel changes in serum creatinine. The aim of the present study was to analyze the utility of serum cystatin C as a marker of renal function in these patients.

Methods

Serum creatinine, serum cystatin C and 24-hour creatinine clearance (CCr) were determined in 50 critically ill patients (age 21–86 years; mean Acute Physiology and Chronic Health Evaluation II score 20 ± 9). They did not have chronic renal failure but were at risk for developing renal dysfunction. Serum cystatin C was measured using particle enhanced immunonephelometry. Twenty-four-hour body surface adjusted CCr was used as a control because it is the 'gold standard' for determining GFR.

Results

Serum creatinine, serum cystatin C and CCr (mean ± standard deviation [range]) were 1.00 ± 0.85 mg/dl (0.40–5.61 mg/dl), 1.19 ± 0.79 mg/l (0.49–4.70 mg/l), and 92.74 ± 52.74 ml/min per 1.73 m2 (8.17–233.21 ml/min per 1.73 m2), respectively. Our data showed that serum cystatin C correlated better with GFR than did creatinine (1/cystatin C versus CCr: r = 0.832, P < 0.001; 1/creatinine versus CCr: r = 0.426, P = 0.002). Cystatin C was diagnostically superior to creatinine (area under the curve [AUC] for cystatin C 0.927, 95% confidence interval 86.1–99.4; AUC for creatinine 0.694, 95% confidence interval 54.1–84.6). Half of the patients had acute renal dysfunction. Only five (20%) of these 25 patients had elevated serum creatinine, whereas 76% had elevated serum cystatin C levels (P = 0.032).

Conclusion

Cystatin C is an accurate marker of subtle changes in GFR, and it may be superior to creatinine when assessing this parameter in clinical practice in critically ill patients.
Dose-dependent transcriptome changes by metal ores on a human acute lymphoblastic leukemia cell line
Authors: Sun Nina N , Fastje Cynthia D , Wong Simon S , Sheppard Paul R , Macdonald Stephanie J , Ridenour Gary , Hyde Juanita D , Witten Mark L
Published: February 2005

The increased morbidity of childhood leukemia in Fallon, Nevada and Sierra Vista, Arizona has prompted great health concern. The main characteristic that these two towns share is the environmental pollution attributed to metal ore from abandoned mining operations. Consequently, we have investigated the transcriptome effects of metal ores from these endemic areas using a human T-cell acute lymphoblastic leukemia cell line (T-ALL). Metal ore from Fallon significantly increased cell growth after 24, 48 and 72 h of incubation at 1.5 mg/mL concentration, as measured by trypan-blue. Sierra Vista ore significantly increased cell growth with 0.15 and 1.5 mg/mL following 72 h of incubation. From human cDNA microarray, results indicate that in total, eight genes, mostly metallothionein (MT) genes, were up-regulated and 10 genes were down-regulated following treatment of the T-ALL cells with 0.15 and 1.5 mg/mL of metal ores at 72 h, in comparison with untreated cells. Twenty-eight metals of both ores were quantified and their presence may be associated with the cell growth rate and dose-dependent activation of transcriptomes in immature T-cells.
Recent advances in understanding transforming growth factor β regulation of orofacial development
Authors: Greene Robert M , Pisano M Michele
Published: February 2005

Members of the transforming growth factor (TGF) family have emerged as critical contributors to the choreography of cellular and tissue interactions underlying morphogenesis of the orofacial region. The TGFs β, and their downstream effector molecules, the Smads, play a pivotal role in normal as well as abnormal development of first branchial arch structures. Components of the TGFβ signal transduction machinery are discussed in relation to regulation of transcription, cell division and tissue differentiation in developing orofacial tissue, as evidence for a functional linkage between the TGFβ and retinoic acid signal transduction pathways during orofacial development.
Hydroxyl radical formation resulting from the interaction of nickel complexes of L-histidine, glutathione or L-cysteine and hydrogen peroxide
Authors: Joshi Seema , Husain M M , Chandra Ramesh , Hasan S K , Srivastava R C
Published: February 2005

L-histidine, L-cysteine, reduced glutathione (GSH) and other bioligands, which are ubiquitously present in biological systems, are recognized as antioxidants. Studies have shown that nickel (II) complexed with these ligands catalyzes the disproportionation of H2O2, leading to the generation of hydroxyl radicals (OH•). However, none of the studies could provide information regarding effective concentrations at which these ligands act either as pro-oxidant or antioxidant. Therefore, the observed paradoxical behaviour of biological antioxidants in nickel-induced oxidative response was evaluated. Benzoic acid (BA) is hydroxylated by OH• radical to form highly fluorescent dihydroxy benzoate (OH-BA). We used this model to study the effect of nickel complexes of L-histidine, GSH or L-cysteine on the hydroxylation of BA. The concentration-dependent effect of L-histidine, GSH and L-cysteine, or nickel on the hydroxylation of BA was studied. The hydroxylation of BA was significantly enhanced up to 1:0.5 molar ratio (Ni:hist or GSH). However, beyond 1:0.5 molar ratios, histidine/GSH inhibited the hydroxylation and complete inhibition was observed at 1:1 molar ratios. Sorbitol and caffeic acid, considered as scavengers of hydroxyl radicals, inhibited nickel-induced hydroxylation of BA. The present study demonstrates paradoxical behaviour of these bioligands. They act as pro-oxidant at lower ligand ratios and as antioxidant at higher ligand ratios. The redox properties of nickel complexes with histidine, GSH or cysteine reported here may be crucial for the toxicity of nlckel.
Electrophysiological safety of DW-286a, a novel fluoroquinolone antibiotic agent
Authors: Kim Eun-Joo , Kim Ki-Suk , Shin Won-Ho
Published: February 2005

Inhibition of the potassium current IKr, and QT prolongation has been known to be associated with drug-induced torsades de pointes arrhythmias (TdP) and sudden cardiac death. We investigated the cardiac electrophysiological effects of DW-286a, a new class of fluoroquinolone antibiotics reported to prolong the QT interval. To investigate the electrophysiological safety of DW-286a, we used conventional microelectrode recording techniques in isolated guinea pig papillary muscles, whole-cell patch clamp techniques in human ether-á-go-go related gene (hERG)-transient transfected Chinese hamster ovary cells, and in vivo electrocardiogram (ECG) measurements in Sprague-Dawley (SD) rats by the use of a telemetry system. DW-286a at 300 μM significantly ( P <0.01) prolonged action potentials at 50% repolarization (APD50) and 90% repolarization (APD90). For IHERG, the IC50 value was 89.00±37.85 μM with a Hill coefficient ( nH) of −0.97 ±0.49. However, when DW-286a was orally administered to conscious SD rats at a high dose (1000 mg/kg), no significant effect on ECG in vivo was detected. From a previous study, we know that concentration at 19.8 μM is the antimicrobial end-point of DW-286a. Therefore, our data suggest that in the electrophysiological aspect, it can be thought that the effective concentrations of DW-286a are between 19.8 and 100 μM (concentration in serum).
Toxicogenomics: regulatory perspective on current position
Authors: Battershill Jon M
Published: February 2005

Published studies on the utility of toxicogenomic approaches (transcriptomics, proteomics and metabonomics) in screening for toxicological mechanisms and evaluation of dose response effects have been reviewed. The information supports the use of transcriptomics to screen for specific toxicological mechanisms for which there is an a priori hypothesis, although in some areas such as mutagenicity testing, toxicogenomics appear to have limited value for identifying mutagens. Data from such screening approaches cannot be used to exclude the possibility of toxicity. Targeted transcriptomics might be valuable for screening for specific mechanisms of toxicity considered to be irrelevant for assessing risk to humans, which would help to reduce the need for detailed testing of some chemicals. An integrated approach is suggested where data from more than one toxicogenomic approach could be used as an adjunct to conventional toxicology to assess dose-response in toxicological tests. An outline preliminary proposal for use by regulators is suggested although it is noted that more data are required before this could be formally used in a decision-making process.
Occupational exposure to aluminium phosphide and phosphine gas? A suspected case report and review of the literature
Authors: Sudakin D L
Published: February 2005

The manufacture and application of aluminium phosphide fumigants pose risks of inhalation exposure to phosphine gas. This article presents a case report of suspected inhalation exposure to phosphine gas in a manufacturing facility for aluminium phosphide fumigants, which was associated with acute dyspnoea, hypotension, bradycardia and other signs of intoxication. These symptoms resolved within several hours after removal from exposure. A review of the data on human exposures to phosphide fumigants identifies both pesticide applicators and individuals in the vicinity of application to be at risk of accidental exposure and injury from phosphine inhalation. More recent reports have identified risks of phosphine gas inhalation in association with the clandestine production of methamphetamine. Toxicodynamic effects of phosphine result from the inhibition of cytochrome c oxidase and subsequent generation of reactive oxygen species. There remain unanswered questions relating to the toxicokinetics of phosphine, as well as the assessment of human exposure utilizing biomarkers. As initial signs and symptoms of intoxication from phosphine gas may be nonspecific and transient, there is a need for improved recognition of the potential hazards associated with phosphide fumigants and phosphine gas.
Cytokine expression in lupus kidneys
Authors: Aringer M , Smolen J S
Published: February 2005

Although far from complete, the picture of cytokines present in systemic lupus erythematosus (SLE) glomerulonephritis is already complex. Proinflammatory cytokines, such as TNF, IL-6, IL-1, and IL-18 are upregulated, as are both Th1 and Th2 cytokines, with different implications. In many instances, the local effects may be different from the systemic immunoregulatory ones. For some proinflammatory cytokines, and TNF in particular, the local proinflammatory ones may be more relevant to the disease. This may help solve discrepancies between different murine models of the disease and provide a better rationale for targeting certain cytokines in human SLE.
Clinical presentation and monitoring of lupus nephritis
Authors: Balow J E
Published: February 2005

The diversity of clinical presentations of lupus nephritis parallel the diversity of pathologic lesions seen in the kidneys of patients with SLE. Renal manifestations range from asymptomatic hematuria or proteinuria to overt nephritic and nephrotic syndromes, rapidly progressive glomerulonephritis, and chronic renal failure. Subclinical nephropathy both during presentation and during monitoring of disease activity is frequently missed because of the notorious unreliability of routine screening urinalyses performed in high-throughput clinical pathology laboratories. Requisitions for urine microscopy should be flagged for special attention in patients at risk for lupus nephritis. Depression of classic complement pathway components and high titers of anti-DNA, anti-nucleosome, or anti-C1q antibodies identify patients are increased risk of renal involvement or flares of nephritis. Several disease activity and damage indexes are available, but they are mostly used in clinical research setting and none has achieved wide use for standard clinical practice.
Pathology of lupus nephritis
Authors: Lewis E J , Schwartz M M
Published: February 2005

The glomerular pathology of lupus nephritis is the result of diverse immune insults which are probably of independent pathogenetic origins. Although lupus nephritis is looked upon as a classic example of immune complex-induced microvascular injury resulting from circulating DNA double stranded polynucleotide antigens/anti-DNA antibody complexes, other mechanisms, including in situ reactivity of free antibody with fixed antigens and the role of sensitized T-cells, are probably an important part of the picture. This complexity makes categorization of glomerular pathology into a clinically relevant classification an important goal so that our experiences can be reliably compared. This review describes the various glomerular lesions commonly encountered in lupus nephritis and, based upon data derived from experimental models, emphasizes the importance of understanding the clinical relevance of the reported morphology. We point out that the severity of glomerular damage is not merely the accrued result of immune complex induced injury to individual capillaries, but involves capillary necrosis and thrombosis, neither of which may have anything to do with immune complexes or immune aggregates. In fact, the segmental lesions of glomerular capillary necrosis and thrombosis may have a great deal to do with the response to therapy and the ultimate outcome of the patient. While discrete morphologic lesions such as mesangiopathy, acute inflammation, necrosis, thrombosis, epimembranous lesions and podocytopathy are readily described, it is important to note that any given case can represent any combination of these insults. In this context, the new proposed International Society of Nephrology Classification is presented and its strengths and weaknesses discussed.
Prognostic factors in lupus nephritis
Authors: Mok C C
Published: February 2005

Systemic lupus erythematosus (SLE) is a heterogeneous disorder and its renal manifestations are protean. The course and prognosis of lupus nephritis is dependent on a large number of demographic, histopathological, serological, racial, socioeconomic and time dependent factors. Moreover, the initial and maintenance therapeutic regimens may also influence the long term renal outcome. This article reviews the important prognostic factors that have been reported in literature. The management strategy of lupus nephritis should be individualized and based on a composite of these parameters.
Optimal care of lupus nephritis patients
Authors: Jadoul M
Published: February 2005

Optimal care of lupus nephritis patients should include the treatment of proteinuria and hypertension, other measures to delay the progression of chronic kidney disease, the vigorous management of cardiovascular risk factors and finally, the treatment of advanced chronic kidney disease and its consequences. These topics are briefly reviewed in the present paper, with particular emphasis on the recent progresses in antiproteinuric treatment.
Novel therapies in lupus nephritis
Authors: Tahir H , Isenberg D A
Published: February 2005

Renal disease continues to cause major morbidity and some mortality for around 30-40% of patients with systemic lupus erythematosus (SLE). Although the combinations of prednisolone and azathioprine or prednisolone and cyclophosphamide have been beneficial to many patients with SLE, they are not always effective and have significant side effects. It is very encouraging that new immunosuppressive drugs such as mycophenolate mofetil and more targeted therapies e.g., anti-CD20 are coming rapidly to larger scale clinical trials. The treatment of lupus nephritis is set to change quite rapidly in the next decade. In this review we highlight the likely major therapeutic advances.
Use of Anti‐CD3 Monoclonal Antibody to Induce Immune Regulation in Type 1 Diabetes
Authors: BISIKIRSKA BRYGIDA C. , HEROLD KEVAN C.
Published: February 2005

Abstract: Achieving immunologic tolerance to autoimmune diabetes is the goal of therapies for treatment and prevention of the disease. However, whether this can be achieved with an antigen‐specific approach is still unproven in humans. Other approaches, including treatment with anti‐CD3 monoclonal antibody, have focused on regulation of an active immune response. Preclinical studies with anti‐CD3 mAb showed the ability to reverse diabetes and induce tolerance to autoimmunity, even at the time of presentation with hyperglycemia. These studies also suggested that mAb treatment induced an active regulatory process. Based on these and other preclinical data, we have carried out a Phase I/II trial of the humanized FcR non‐binding anti‐CD3 mAb hOKT3γ1(Ala‐Ala) in patients with new‐onset type 1 diabetes. mAb treatment prevented the loss of insulin production over the first two years of the disease with reduced hemoglobin A1c levels and insulin usage. Studies have suggested that the mechanism of drug action involves induction of regulatory cells. CD4+IL‐10+ T cells can be found in patients after treatment; in addition, the CD8+ T cells are induced by the mAb, and these cells may regulate antigen‐ specific responses. These initial studies have shown clinical efficacy of treatment with anti‐CD3 mAb and suggest a novel mechanism that may account for the lasting effects of treatment.
Detection of Autoreactive T Cells in Type 1 Diabetes Using Coded Autoantigens and an Immunoglobulin‐Free Cytokine ELISPOT Assay: Report from the Fourth Immunology of Diabetes Society T Cell Workshop
Authors: NAGATA MASAO , KOTANI REIKO , MORIYAMA HIROAKI , YOKONO KOICHI , ROEP BART O. , PEAKMAN MARK
Published: February 2005

Abstract: The “gold standard” for evaluation of immunoassays is blinded testing, using coded samples and antigens. Although assays for autoreactive T cells are no exception to this rule, it is nonetheless rarely applied in this context. To facilitate such investigations, we coded a panel of 10 peptides representing T cell epitopes reported to be of relevance to islet autoimmunity. These were deployed in a novel cytokine ELISPOT assay, in which the use of immunoglobulin‐free medium reduces background reactivity and thus potentially enhances the specificity and sensitivity of detection of autoreactive T cells. Significant IFN‐γ production against GAD65 (554‐575), insulin (B9‐23), and IA‐2 (709‐736) peptides were observed in type 1 diabetic patients, whereas no significant changes from background were detected in healthy controls. These results confirm the utility of the blinded performance of T cell assays as the most robust platform for assessing technologies to T cell autoreactivity.
CD4+ T Cell Proliferation in Response to GAD and Proinsulin in Healthy, Pre‐diabetic, and Diabetic Donors
Authors: MANNERING STUART I. , MORRIS JESSICA S. , STONE NATALIE L. , JENSEN KENT P. , VAN ENDERT PETER M. , HARRISON LEONARD C.
Published: February 2005

Abstract: The ability to measure proliferation of autoantigen‐specific T cells is critical for the evaluation of cellular immune function. Using a novel, sensitive, CFSE‐based assay, we were able to directly quantitate autoantigen‐specific CD4+ T cell proliferation. However, peripheral blood cells from healthy, pre‐diabetic and diabetic donors exhibited overlap in responses to glutamic acid decarboxylase (GAD65) and proinsulin (PI). This indicates that autoantigen‐induced CD4+ T cell proliferation in a functionally complex cell population may not discriminate disease in the general population. Clear discrimination was found between diabetic and healthy sibs, suggesting the need to standardize the genetic and environmental background. In addition, the ability of the CFSE assay to allow analysis of the phenotype and function of autoantigen‐responsive T cells may improve discrimination.
Enhancing the Sensitivity of Assays to Detect T Cell Reactivity: The Effect of Cell Separation and Cryopreservation Media
Authors: TREE TIMOTHY I.M. , ROEP BART O. , PEAKMAN MARK
Published: February 2005

Abstract: The identification of sensitive assay formats capable of distinguishing islet autoreactive T cells directly ex vivo in blood is a major goal in type 1 diabetes research. Whereas much effort has been made to identify suitable assay formats, relatively little attention has been paid to optimizing the quality of cell preparations used. To address this issue we investigated the role of two key variables in the preparation of peripheral blood mononuclear cells (PBMCs): the separation media used in density gradient centrifugation and the method of cryopreservation. PBMCs were prepared from a single individual using different protocols and tested for responses to suboptimal concentrations of tetanus toxoid, representing a low frequency recall response. Significant differences were observed in T cell responses dependent upon the selection of the separation media and cryopreservation methods used, indicating that relatively small differences in preparation of PBMCs can have measurable effects on assay sensitivity.
New Approaches forin SilicoIdentification of Cytokine‐Modified β Cell Gene Networks
Authors: KUTLU BURAK , NAAMANE NAJIB , BERTHOU LAURENCE , EIZIRIK DECIO L.
Published: February 2005

Abstract:Beta cell dysfunction and death in type 1 diabetes mellitus (T1DM) is caused by direct contact with activated macrophages and T lymphocytes and by exposure to soluble mediators secreted by these cells, such as cytokines and nitric oxide. Cytokine‐induced apoptosis depends on the expression of pro‐ and anti‐apoptotic genes that remain to be characterized. Using microarray analyses, we identified several transcription factor and “effector” gene networks regulated by interleukin‐1β and/or interferon‐γ in β cells. This suggests that β cell fate following exposure to cytokines is a complex and highly regulated process, depending on the duration and severity of perturbation of key gene networks. In order to draw correct conclusions from these massive amounts of data, we need to utilize novel bioinformatics and statistical tools. Thus, we are presently performingin silicoanalysis for the localization of binding sites for the transcription factor NF‐κB (previously shown to be pivotal for β cell apoptosis) in 15 temporally related gene clusters, identified by time‐course microarray analysis.In silicoanalysis is based on a broad range of computational techniques used to detect motifs in a DNA sequence corresponding to the binding site of a transcription factor. These computer‐based findings must be validated by use of positive and negative controls, and by “ChIP on chip” analysis. Moreover, new statistical approaches are required to decrease false positive findings. These novel approaches will constitute a “proof of principle” for the integrated use of bioinformatics and functional genomics in the characterization of relevant cytokine‐regulated β cell gene networks leading to β cell apoptosis in T1DM.
Differential Expression of Nonislet Autoimmunity: Comparison of Korean and U.S. Patients with Type 1 Diabetes
Authors: PARK YONGSOO , KIM SINKYU , PARK SUKYUNG , KIM TAEWHA , YU LIPING , REWERS MARIAN , EISENBARTH GEORGE S.
Published: February 2005

Abstract: Type 1 diabetes (T1D) is frequently associated with other autoimmune diseases. The occurrence of common features of autoimmune diseases and the coassociation of multiple autoimmune diseases in the same individual or family support the notion that there may be common genetic factors. We previously reported that immunogenetic markers of T1D were similar in Korean and U.S. families. We hypothesized that nonislet autoimmunity might be expressed in a similar manner in Korean as well as in Caucasian patients and correlated with the DRB1‐DQB1 haplotypes. Twenty‐five percent of Korean patients with T1D (32/128) had antithyroid autoantibodies (ATA+), whereas eight percent of age‐matched controls were ATA+ [OR = 3.7 (95% CI:1.0‐12.0), P < 0.05]. Twenty‐three percent (84/369) of age‐matched T1D patients from the U.S. had ATA (not statistically different from that in Koreans). None of the Korean patients nor the family members were positive for 21‐hydroxylase (21OH) or transglutaminase autoantibodies (TG). In contrast, in U.S. patients, nine T1D patients (2.4%) were 21OH+ (not statistically different from that in Koreans) and 39 T1D patients (10.6%) were TG+ [OR = 30.7 (95% CI: 4.6‐111), P < 10−4 vs. Korean patients]. Nonislet autoimmunity is prevalent in Korean and U.S. patients with T1D and their family members, but specific forms of autoimmunity differ even after matching for their HLA haplotypes. Individuals with T1D and their relatives frequently develop a panel of autoantibodies, perhaps due to other common susceptibility genes that are shared among first‐degree relatives.
Stromal Cell‐Derived Factor‐1 Chemokine Gene Variant in Patients with Type 1 Diabetes and Autoimmune Thyroid Disease
Authors: KAWASAKI EIJI , IDE AKANE , ABIRU NORIO , KOBAYASHI MASAKAZU , FUKUSHIMA TETSUYA , KUWAHARA HIRONAGA , KITA ATSUSHI , UOTANI SHIGEO , YAMASAKI HIRONORI , EGUCHI KATSUMI
Published: February 2005

Abstract: Type 1 diabetes is a heterogenous autoimmune disease and is frequently associated with other organ‐specific autoimmune diseases, including autoimmune thyroid disease (AITD). Type 1 diabetic patients with AITD are known to have clinical and immunological features distinct from patients without AITD. This study investigated whether stromal cell‐derived factor (SDF)‐1 gene polymorphism is associated with susceptibility to type 1 diabetes and AITD. SDF‐1 is a powerful chemokine that upregulates T‐cell migration and activation, and the gene for SDF‐1 is located near type 1 diabetes susceptibility locus IDDM10. The SDF1‐3′A variant (801 G to A in the 3′‐untranslated region) was determined by the PCR‐RFLP technique in 54 type 1 diabetic patients with AITD, 75 type 1 diabetic patients without AITD, 137 nondiabetic patients with AITD, and 106 healthy subjects in a case‐control study. No significant differences on the allele and genotype frequencies of the SDF1 gene polymorphism were found, not only in type 1 diabetic patients with AITD compared with normal controls but also between nondiabetic patients with AITD and healthy control subjects. These results suggest that the SDF1‐3′A variant is not associated with genetic susceptibility to type 1 diabetic patients and AITD.
Infant Vitamin D Supplementation and Allergic Conditions in Adulthood: Northern Finland Birth Cohort 1966
Authors: HYPPöNEN ELINA , SOVIO ULLA , WJST MATTHIAS , PATEL SWATEE , PEKKANEN JUHA , HARTIKAINEN ANNA‐LIISA , JäRVELINB MARJO‐RIITTA
Published: February 2005

Abstract: Allergen‐induced secretion of Th2‐type cytokines and IgE production have recently been reported to be increased in mice treated with 1,25(OH)2D, the active form of vitamin D. Our objective was to investigate whether vitamin D supplementation in infancy is associated with the risk of atopy, allergic rhinitis, and asthma. The Northern Finland Birth Cohort consists of all individuals in the two most northern provinces of Finland who were due to be born in 1966. Data on vitamin D supplementation during the first year of life was obtained in 1967. Current asthma and allergic rhinitis were reported at age 31 years (n= 7,648), and atopy determined by skin‐prick test in a sub‐sample still living in northern Finland or the Helsinki area (n= 5,007). The prevalence of atopy and allergic rhinitis at age 31 years was higher in participants who had received vitamin D supplementation regularly during the first year compared to others (OR 1.46, 95%CI 1.4‐2.0, and OR 1.66, 95%CI 1.1‐1.6, respectively). A similar association was observed for asthma (OR 1.35, 95%CI 0.99‐1.8). These associations persisted after adjustment for a wide range of behavioral and social factors (adjusted: OR 1.33 for all, P= 0.01 for atopy, P= 0.001 for allergic rhinitis, and P= 0.08 for asthma). We observed an association between vitamin D supplementation in infancy and an increased risk of atopy and allergic rhinitis later in life. Further study is required to determine whether these observations reflect long‐term effects on immune regulation or differences in unmeasured determinants of vitamin D supplementation.
Is Type 1 Diabetes in the Japanese Population the Same as among Caucasians?
Authors: KAWASAKI EIJI , EGUCHI KATSUMI
Published: February 2005

Abstract: In the Japanese population, the incidence of type 1 diabetes is as low as ∼2 cases/year/100,000 children, which is much lower compared to that in countries with populations predominantly of Caucasian origin. However, the prevalences of anti‐islet autoantibodies in patients with Japanese type 1 diabetes are 60‐70% for GAD autoantibodies, 45‐50% for insulin autoantibodies (IAA), and 60‐65% for IA‐2 autoantibodies at disease onset, which are similar to those reported in Caucasian patients. With combinatorial analysis of these autoantibodies, 90% of patients express at least one of these autoantibodies and are classified as type 1A diabetics. There is a significant number of patients with latent autoimmune diabetes in adults (LADA) in Japan, and a high level of GAD autoantibodies has a high predictive value for future insulin deficiency in such patients. Recently, it has been reported that a group of extremely rapid‐onset patients presented with diabetic ketoacidosis and a low HbA1c level, called fulminant diabetes mellitus. Although they had severe hyperglycemia, these individuals lacked the expression of anti‐islet autoantibodies. With a nationwide survey, it was documented that fulminant type 1 diabetes accounts for ∼20% of the ketosis‐onset patients with type 1 diabetes in Japan. It is currently unknown whether the pathogenesis of fulminant type 1 diabetes is associated with autoimmune response to pancreatic islet β cells. Japanese patients with type 1 diabetes are clinically heterogeneous, and further investigations are required to clarify the underlying pathogenesis for each subgroup of type 1 diabetes.
Mothers' Attachment Insecurity and Diabetes‐Related Autoantibodies in Their Infants
Authors: SEPA ANNELI , FRODI ANN , LUDVIGSSON JOHNNY
Published: February 2005

Abstract: Psychological stress may, via hormonal levels, increase insulin resistance. The aim of this study was to investigate whether mothers' attachment insecurity is associated with the induction or progression of diabetes‐related autoimmunity in early childhood. Adult attachment interviews were conducted with 18 mothers of infants who were positive, and 32 mothers of infants who were negative, for glutamic acid decarboxylase, selected from ABIS, a large prospective population‐based project. The proportion of children with insecure mothers was larger, but not significantly so, in the autoantibody‐positive group than in the negative group. If an association exists between maternal attachment insecurity and diabetes‐related autoimmunity during infancy, it does not appear to be strong.
Prevalence of Diabetes‐Associated Autoantibodies in Schoolchildren: The Karlsburg Type 1 Diabetes Risk Study
Authors: SCHLOSSER MICHAEL , STREBELOW MARTINA , RJASANOWSKI ILONA , KERNER WOLFGANG , WASSMUTH RALF , ZIEGLER MANFRED
Published: February 2005

Abstract: This study attempts to assess the prevalence of diabetes‐associated autoantibodies in a general population in the northeastern part of Germany, with emphasis on autoantibodies against glutamic acid decarboxylase (GADA), protein tyrosine phosphatase (IA‐2A), and insulin (IAA) by radioassays ≥ 98th percentile, and AAbs binding on pancreatic sections (ICA) by immunofluorescence ≥ 10 Juvenile Diabetes Foundation units. From a total of 11,840 schoolchildren tested for all four AAbs, 821 (6.9%) children were positive for single AAbs, whereas 83 (0.7%) had multiple AAbs. If the primary screening were performed by testing GADA/IA‐2A/IAA, 94% of probands with single AAbs and all with multiple AAbs would be identified. The combinations of GADA/IA‐2A, GADA/IAA, and IA‐2A/IAA would identify 97.6, 98.8, and 85.5% of probands with multiple AAbs, respectively. Thus, combined AAb screening in the general population identifies those probands at risk for diabetes.
Prevalence of GAD65 Antibodies in Lean Subjects with Type 2 Diabetes
Authors: Unnikrishnan A. G. , Singh S. K. , Sanjeevi C. B.
Published: February 2005

Abstract: While type 2 diabetic subjects in developed countries are predominantly obese or overweight, those in India are often nonobese or lean. The reasons for leanness in these subjects has not been well understood. We assessed the prevalence of pancreatic islet autoimmunity in 83 lean adult subjects (BMI < 18.5 kg/m2) with type 2 diabetes by measuring antibodies to glutamic acid decarboxylase‐65 (GAD Abs). Positivity to GAD Ab was present in 21 (25.3%) subjects. In addition, subjects with GAD Ab positivity were younger and had lower beta cell function (homeostasis model assessment, HOMA) as compared to the GAD Ab‐negative group. This suggests that the antibody‐positive group could have a slowly progressive form of type 1 diabetes.
No Association of INS‐VNTR Genotype and IAA Autoantibodies
Authors: DE NANCLARES GUIOMAR PÉREZ , BILBAO J. RAMÓN , CASTAŃO LUIS
Published: February 2005

Abstract: Type 1 diabetes is associated with autoimmune responses against insulin, with insulin autoantibodies (IAA) being a hallmark of the disease. Genetic susceptibility to type 1 diabetes is polygenic and includes the INS VNTR‐IDDM2 locus, which has been shown to regulate the expression of insulin in the pancreas and thymus. In order to determine whether insulin autoimmunity could be attributed to a genetic susceptibility conferred by the INS‐VNTR (IDDM2) locus, we studied the frequency of INS‐VNTR alleles and the presence of IAA in 90 patients with new‐onset type 1 diabetes. IAA were detected in 49 of 67 class I/I individuals and 19 of 23 class III/X patients, indicating that there is no association between the INS VNTR‐IDDM2‐susceptible allele and humoral autoimmunity against insulin. This finding does not support the hypothesis of an allele‐specific tolerance induction that could determine susceptibility toward autoimmunity against the insulin protein and subsequently the development of type 1 diabetes.
Frequency of MICA in All Babies in Southeast Sweden (ABIS) Positive for High‐Risk HLA‐DQ Associated with Type 1 Diabetes
Authors: GUPTA M. , LUDVIGSSON J. , SANJEEVI C. B.
Published: February 2005

Abstract: Type 1 diabetes mellitus (T1DM) is an autoimmune disease known to occur in genetically susceptible individuals after exposure to certain unknown environmental factors. HLA‐DR3‐DQ2 or DR4‐DQ8 are established genetic markers for the disease. MHC class I chain‐related gene‐A (MICA) gene polymorphism has been proposed to be associated with T1DM. To identify the environmental factors and for implementing intervention trials to prevent T1DM, it is important to screen subjects at genetically increased risk for developing T1DM. The All Babies in Southeast Sweden (ABIS) study aims to assess the risk of future progression to T1DM in the general child population. In the present report, we studied the frequency of MICA alleles among newborn babies carrying high‐risk HLA DQ2 or DQ8. Of 2821 newborns, we found 563 subjects positive for DQ2, 583 subjects positive for DQ8, 133 subjects positive for DQ2‐DQ8 (heterozygous), and 1013 subjects positive for either DQ2 or DQ8. Of these 1013 babies, we typed 499 babies for MICA. Frequency of MICA5 was 38% among DQ8+, 35% among for DQ2‐DQ8 (heterozygous) positives, and 22.5% among DQ2+ babies. Frequency of MICA5.1 was 81% among DQ+, 62% among DQ8+, and 71% among DQ2‐DQ8 (heterozygous) positives. Frequency of MICA6 was between 20% and 22% among the three groups. Frequency of MICA5/5.1 was 19% among DQ2‐DQ8 (heterozygous) positives and between 12% and 13% among those positive for DQ2, DQ8, DQ2, or DQ8. The results from genetic typing in this study would be useful, in conjunction with results from autoantibody analysis that are prospectively being followed‐up in all the babies, to develop an approach for identifying children at risk for developing T1DM. Inclusion of MICA typing in addition to HLA could be useful for screening of genetic markers associated with T1DM.
Molecular Pathways Altered by Insulin B9‐23 Immunization
Authors: ECKENRODE SARAH E. , RUAN QING‐GUO , COLLINS CHRISTIN D. , YANG PING , MCINDOE RICHARD A. , MUIR ANDREW , SHE JIN‐XIONG
Published: February 2005

Abstract: Type 1 diabetes (T1D) in the nonobese diabetic (NOD) mouse can be delayed by administration of insulin or specific insulin peptides. To better understand how insulin treatment delays diabetes development, NOD mice treated with an insulin peptide (B9‐23) were compared with age‐matched NOD and NOD congenic mice for gene expression changes in spleen using cDNA microarray. Fifty genes were identified that were significantly altered by B9‐23 treatment. Thirty‐three of these genes are downregulated by the treatment while they are upregulated during the natural disease progression in NOD from immature (3‐4 weeks) to mature (10 weeks) stages. Taken together, our data suggest that the B9‐23 treatment, like the protective genes in NOD congenic strains, reduces pro‐inflammatory activation of lymphocytes that normally occurs in NOD mice. Furthermore, our studies discovered two genes (Irf4 and Tra1) with increased expression in B9‐23‐treated mice that promote the Th2 response, providing a molecular basis for the B9‐23‐protective therapy.
Establishment of Native Insulin‐Negative NOD Mice and the Methodology to Distinguish Specific Insulin Knockout Genotypes and a B:16 Alanine Preproinsulin Transgene
Authors: NAKAYAMA MAKI , MORIYAMA HIROAKI , ABIRU NORIO , BABU SUNANDA R. , SIKORA KAMILA , LI MARCELLA , MIAO DONGMEI , HUTTON JOHN C. , ELLIOTT JOHN F. , EISENBARTH GEORGE S.
Published: February 2005

Abstract: We hypothesize that NOD mice without native insulin, but with an altered insulin B:9‐23 sequence, will be completely protected from diabetes/insulitis if insulin B:9‐23 is an essential T cell epitope. To investigate this hypothesis, we have established initial insulin 1‐ and 2‐negative NOD mice with a transgene directing production of preproinsulin with alanine at position B:16 rather than the native tyrosine of both insulin 1 and insulin 2. Sets of primers for PCR‐based assays have been created and validated. They are able to distinguish the presence or absence of the insulin gene knockouts and of both native insulin 1 and insulin 2 (and thus distinguish heterozygous versus homozygous knockouts), as well as the presence of the altered insulin transgene, B:16 alanine preproinsulin. Four B:16 alanine transgenic founders were produced directly in NOD mice and, by intercrossing, initial live native insulin‐negative B:16 alanine transgenic mice have been generated.
The Power of an Integrated Informatic and Molecular Approach to Type 1 Diabetes Research
Authors: PETROVSKY NIKOLAI , SILVA DIEGO
Published: February 2005

Abstract: Recent years have witnessed an explosive growth in available biological data. This includes a tremendous quantity of sequence data (e.g., biological structures, genetic and physical maps, pathways) generated by genome and transcriptome projects focused on humans, mice, and a multitude of other species. Diabetes research stands to greatly benefit from this data, which is distributed across public and private databases and the scientific literature. The increasing quantity and complexity of this biological data necessitates use of novel bioinformatics strategies for its efficient retrieval, analysis, and interpretation. Bioinformatic capability is becoming increasingly indispensable for fast and comprehensive analysis of biological data by diabetes researchers. There is great potential for diabetes scientists and clinicians to take advantage of recent bioinformatics and knowledge discovery developments to radically transform and advance this field of research. This paper will review advances in the field of bioinformatics relevant to diabetes research and preview a new specialty diabetes database, Diaβeta, that we are creating to serve as a central bioinformatic portal for type 1 diabetes research, as well as serving as a public repository for β cell gene and protein expression data.
Randomized Comparison of Low Molecular Weight Heparin and Coumarin Derivatives on the Survival of Patients With Cancer and Venous Thromboembolism
Authors: Lee Agnes Y.Y. , Rickles Frederick R. , Julian Jim A. , Gent Michael , Baker Ross I. , Bowden Chris , Kakkar Ajay K. , Prins Martin , Levine Mark N.
Published: February 2005

Purpose

Experimental studies and indirect clinical evidence suggest that low molecular weight heparins may have antineoplastic effects. We investigated the influence of a low molecular weight heparin dalteparin on the survival of patients with active cancer and acute venous thromboembolism.

Patients and Methods

Survival data were examined in a posthoc analysis in patients with solid tumors and venous thromboembolism who were randomly assigned to dalteparin or a coumarin derivative for 6 months in a multicenter, open-label, randomized, controlled trial. All-cause mortality at 12 months was compared between treatment groups in patients with and without metastatic malignancy. The effect of dalteparin on survival was compared between the two patient subgroups.

Results

During the 12-month follow-up period, 356 of 602 patients with solid tumors and acute venous thromboembolism died. Among patients without metastatic disease, the probability of death at 12 months was 20% in the dalteparin group, as compared with 36% in the oral anticoagulant group (hazard ratio, 0.50; 95% CI, 0.27 to 0.95; P = .03). In patients with metastatic cancer, no difference in mortality between the treatment groups was observed (72% and 69%, respectively; hazard ratio, 1.1; 95% CI, 0.87 to 1.4; P = .46). The observed effects of dalteparin on survival were statistically significantly different between patients with and without metastatic disease (P = .02).

Conclusion

The use of dalteparin relative to coumarin derivatives was associated with improved survival in patients with solid tumors who did not have metastatic disease at the time of an acute venous thromboembolic event. Additional studies are warranted to investigate these findings.