bluuebunny/crossref_metadata_2025 huggingface dataset:
Type II Cryoglobulinemia Is Not Associated with Hepatitis C Infection
Authors: TERVAERT J.W. COHEN , Van PAASSEN P. , DAMOISEAUX J.
Published: September 2007

Abstract:  Mixed cryoglobulinemia (MC) are cryoprecipitable immunocomplexes. In type II MC, a combination of polyclonal and monoclonal immunoglobulins is found, whereas in type III a combination of polyclonal immunoglobulins is detected. MC is usually associated with hepatitis C (HCV) infection as has been found in studies that have been performed in countries with a high prevalence of HCV. Because HCV has an extremely low prevalence in the Netherlands (<0.1% of the population), we wondered whether HCV is also associated with MC in our regional referral center. To answer this question, we tested consecutive patients with type II MC for HCV antibodies and for HCV‐mRNA by polymerase chain reaction (PCR). Between January 2000 and June 2005, 22 patients tested positive for type II MC. Seven patients had essential MC, 2 patients had MC due to a lymphoproliferative disease, 10 patients had MC in the context of a systemic autoimmune disease, and 3 patients had MC without a clear diagnosis. HCV antibodies were not detected in any of the 22 patients. Also, all samples tested negative for HCV‐mRNA. During follow‐up none of these patients developed an HCV infection. In summary, the estimated occurrence of HCV in 60–90% of patients with MC is not found in our region where MC is only infrequently associated with HCV. In a substantial proportion of our patients a really “essential MC” is observed. A search for yet unknown etiological factors is clearly needed in these patients, who frequently have severe renal involvement warranting aggressive immunosuppressive therapy.
Systemic Multifocal Epithelial Inflammations Associated with PBC‐like Bile Duct Damage in Chronic Colitis–Harboring TCRα−/−×AIM−/− Mice
Authors: HARUTA IKUKO , HASHIMOTO ETSUKO , KOBAYASHI MAKIO , SHIRATORI KEIKO
Published: September 2007

Abstract:  Autoimmune disorder and associated multifocal organ inflammations such as dry gland syndrome are occasionally observed; however, their etiologies are not clearly understood. We previously reported that chronic colitis–harboring TCRα−/−×AIM−/− mice show primary biliary cirrhosis (PBC)‐like bile duct damage in the liver. Gram‐positive bacterial infection is one of the candidates for the pathogenesis of PBC. We also reported that the bacterial cell wall component lipoteichoic acid (LTA) was detected at the sites of inflammation around damaged bile ducts in PBC patients. On the basis of these facts, we hypothesized that LTA might affect the pathogenesis of bile duct damage in the livers of TCRα−/−×AIM−/− mice. LTA was detected not only in the portal area with inflammation in the liver but also throughout the gastrointestinal tract, from the stomach to the colon, and especially in the epithelium at sites of inflammation. In addition, LTA was detected around both pancreatic ducts with inflammation and at the distal renal tubules with inflammation in TCRα−/−×AIM−/− mice. Furthermore, in the liver, pancreas, kidney, and colon, fibrous stroma were detected at the sites of LTA‐positive inflammation foci. Bacterial LTA might affect the pathogenesis of epithelial inflammation followed by fibrosis in systemic multifocal epithelial inflammations in chronic colitis–harboring TCRα−/−×AIM−/− mice with PBC‐like bile duct damage.
Aluminum Is a Potential Environmental Factor for Crohn's Disease Induction
Authors: LERNER AARON
Published: September 2007

Abstract:  Aluminum (Al) is a common environmental compound with immune‐adjuvant activity and granulomatous inflammation inducer. Al exposure in food, additives, air, pharmaceuticals, and water pollution is ubiquitous in Western culture. Crohn's disease (CD) is a chronic relapsing intestinal inflammation in genetically susceptible individuals and is influenced by yet unidentified environmental factors. It is hypothesized, in the present review, that Al is a potential factor for induction or maintaining the inflammation in CD. Epidemiologically, CD incidence is higher in urban areas, where microparticle pollution is prevalent. Al immune activities share many characteristics with the immune pathology of CD: increased antigen presentation and APCs activation, many luminal bacterial or dietary compounds can be adsorbed to the metal and induce Th1 profile activity, promotion of humoral and cellular immune responses, proinflammatory, apoptotic, oxidative activity, and stress‐related molecule expression enhancement, affecting intestinal bacterial composition and virulence, granuloma formation, colitis induction in an animal model of CD, and terminal ileum uptake. The Al–bacterial interaction, the microparticles homing the intestine together with the extensive immune activity, put Al as a potential environmental candidate for CD induction and maintenance.
Spectrum of Autoantibodies in Tunisian Adult Type 1 Diabetes Mellitus
Authors: LAADHAR LILIA , ZITOUNI MONDHER , KALLEL‐SELLAMI MARYAM , BOUGUERRA RADHIA , CHAABOUNI HATEM , MAKNI SONDES
Published: September 2007

Abstract:  As an autoimmune disease, type 1 diabetes mellitus (T1DM) is characterized by the presence of several autoantibodies. The aim of this study was to examine a broad spectrum of antibodies in Tunisian adult T1DM and to compare their prevalence with a healthy control group. Two hundred sixty‐one diabetics and 100 healthy blood donors were enrolled in this study. Indirect immunofluorescence was performed for the detection of islet cell, antiendomysial, antinuclear, antimitochondrial, antismooth muscle, antireticulin, and antikeratin antibodies. Enzyme‐linked immunosorbent assay was used for measuring anticardiolipin, antigliadin, antitransglutaminase, and antithyroperoxidase antibodies. Latex agglutination was used for the detection of rheumatoid factors. As expected, islet cell antibodies were the most frequent (33.7%). Antigliadin, antithyroperoxidase, and antikeratin antibodies were relatively frequent (18%, 15.3%, and 10.3%, respectively) and were statistically more prevalent in diabetics than in controls. There was no correlation between diabetes duration and any autoantibody, except for islet cell antibodies that were more frequent at the onset of diabetes. Several autoantibodies nonspecific of diabetes are frequent in diabetic patients, which may be associated with or predictors of some autoimmune diseases, and can also reflect a special profile of autoimmunity in diabetics in comparison to healthy controls.
Circulating CD4+CD25high Regulatory T Cells and Natural Killer T Cells in Children with Newly Diagnosed Type 1 Diabetes or with Diabetes‐Associated Autoantibodies
Authors: ÖLING VIVEKA , MARTTILA JANE , KNIP MIKAEL , SIMELL OLLI , ILONEN JORMA
Published: September 2007

Abstract:  Type 1 diabetes is a T‐cell–mediated autoimmune disease in which insufficient regulatory mechanisms are perceived to be involved in the pathogenesis. We used flow cytometry to analyze the proportion of CD4+CD25high regulatory T cells and natural killer T (NKT) cells in peripheral blood obtained from 25 children with newly diagnosed type 1 diabetes, 21 nondiabetic subjects positive for two or more diabetes‐associated autoantibodies, and from 39 autoantibody‐negative age‐ and HLA‐matched control subjects. CD4+CD25high T cells were also stained for additional markers HLA‐DR, CD69, and CD62L. As NKT cell markers, we used CD161, Vβ11, and Vα24. The frequency of CD4+CD25highHLA‐DR− T cells was significantly higher in multiple autoantibody‐positive children than in controls (P= 0.021). We also detected a significantly higher level of CD4+CD25highHLA‐DR− and CD4+CD25highCD69− T cells among children expressing three to four autoantibodies when compared to the controls (P= 0.004 and P= 0.048, respectively). The proportions of CD161+Vβ11+ or Vα24+Vβ11+ NKT cells were similar in all three groups of children studied. Interestingly, children with only two autoantibodies had a higher level of CD161+Vβ11+ NKT cells than the controls (P= 0.002). Our data might be interpreted as indicative of an intensified regulatory response of regulatory T cells and NKT cells during the preclinical phase of the disease.
CD40 Is Required for Development of Islet Inflammation in the RIP‐CD154 Transgenic Mouse Model of Type 1 Diabetes
Authors: HAASE CLAUS , MARKHOLST HELLE
Published: September 2007

Abstract:  Type 1 diabetes is believed to be an autoimmune disease where cells of the immune system destroy the insulin‐producing β cells in the islets of Langerhans. The trigger(s) of the inflammatory reaction is yet unknown, but both genetic and environmental factors, including viruses or other pathogens, are thought to play a role. We have recently described a transgenic mouse model—the RIP‐CD154 mouse—in which β‐cell–specific expression of CD154 (CD40 ligand) mediates immune activation, insulitis, and diabetes on a non–diabetes‐prone background. By the use of bone marrow chimeric mice, we now demonstrate that a functional Cd40 gene is necessary for islet inflammation and we show that CD40 expression on bone marrow–derived cells is sufficient to trigger activation of the immune system and development of insulitis.
Modulation of Acute and Chronic Inflammation of the Lung by GITR and its Ligand
Authors: NOCENTINI GIUSEPPE , CUZZOCREA SALVATORE , BIANCHINI RODOLFO , MAZZON EMANUELA , RICCARDI CARLO
Published: September 2007

Abstract: Glucocorticoid‐induced TNFR‐related (GITR) protein, a member of the tumor necrosis factor receptor superfamily, is expressed in many components of the innate and adaptive immune system and modulates their activation following interaction with its ligand (GITRL). Here we review and discuss results described in previous publications where the role of the GITR/GITRL system in lung inflammation was evaluated using two experimental systems. We also discuss the proinflammatory role played by the GITR/GITRL system and the potential use of GITR fusion protein in inhibiting inflammation.
Measuring Outcomes in PAH
Authors: FURST DANIEL E.
Published: September 2007

Abstract:  Pulmonary arterial hypertension (PAH) has poor prognosis in systemic sclerosis (SSc), and at present the “gold standard” for diagnosis and follow‐up of PAH in SSc is right heart catheterization (RHC) but it would be very useful to have a noninvasive way to follow these patients. Using the OMERACT criteria for validation of measures of response, the only fully validated measure for PAH in SSc has been the 6‐min walking test. Multiple other measures are particularly valid (e.g., echocardiography, brain natriuretic protein [BNP], FV/DLCO) while a few are unlikely ever to be validated for various reasons (e.g., symptoms, MRA). A Delphi exercise among 78 experts (EPOSS) has been done and has developed a consensus document consisting of eight domains (lung vascular/PAP, exercise capacity, cardiac function, dyspnea, discontinuation of treatment, quality of life, lung parenchymal, and global state), which can be used and must be tested.
Autosensitization as a Pathomechanism in Asthma
Authors: GARN HOLGER , MITTERMANN IRENE , VALENTA RUDI , RENZ HARALD
Published: September 2007

Abstract:  Recent observations indicate that autoimmune disorders and allergies are more closely connected to each other than traditionally considered. Both diseases are characterized by a break of immunological tolerance and in both Th1‐ and Th2‐driven mechanisms may be involved. Moreover, patients suffering from severe chronic atopic diseases have been shown to develop autoreactive antibodies and vice versa autoreactive IgE antibodies may contribute to the perpetuation of allergic immune responses. However, animal models for the investigation of the underlying mechanisms have not been available so far. Here we demonstrate that allergic sensitization and subsequent airway aerosol challenge of mice to a potential autoantigen leads to an allergic airway inflammation and chronic exposure of sensitized mice to a foreign allergen induces autoreactive antibodies. Thus, autoreactive immune mechanisms may be induced either by molecular mimicry or as a consequence of chronic allergic inflammatory processes and these reactivities may then possibly contribute to the perpetuation of allergic immune responses even in the absence of exogenous allergens and to the development of autoimmune diseases.
Rheumatic Fever
Authors: GUILHERME L. , KALIL J.
Published: September 2007

Abstract:  Rheumatic fever (RF) is triggered by S. pyogenes and affects 3–4% of untreated susceptible children. The immune response against streptococcal antigens can lead cross‐recognition of heart tissue proteins resulting in rheumatic heart disease (RHD). HLA class II alleles have been associated with the development of RF/RHD. Tumor necrosis factor (TNF)‐α is also located in the same chromosomal region of HLA genes and has been investigated in RHD patients from Mexico, Turkey, and Brazil. Associations with the TNFA‐308 allele were found and probably are related to the development of valvular lesions. A deficient mannose‐binding lectin (MBL) allele was found in Brazilian patients. MBL is a protein important for the first line of host defense against the bacteria. The association with diverse genes probably indicates a role of certain molecules in both the innate and adaptive immune response. Antigen‐presenting cells bearing the HLA‐DR7 molecule from RHD patients preferentially recognized a heart‐tissue protein cross‐reactive M5 (81–96) peptide. The same peptide was also recognized by heart tissue T cell clones. Cardiac myosin peptides were recognized by high numbers of intralesional T cell clones. The cytokine pattern of infiltrating mononuclear cells in both myocardium and valvular tissue showed a predominance of proinflammatory cytokines (TNF‐α and IFN‐γ) and scarce production of regulatory cytokines, such as IL‐4, in the valve tissue. IL‐10, a predominant regulatory cytokine, was also secreted by large numbers of cells in both valve and myocardium tissue. Data here indicate the complexity of immune reactions leading to autoimmune lesions in RF/RHD.
Measurement of Residual Breast Cancer Burden to Predict Survival After Neoadjuvant Chemotherapy
Authors: Symmans W. Fraser , Peintinger Florentia , Hatzis Christos , Rajan Radhika , Kuerer Henry , Valero Vicente , Assad Lina , Poniecka Anna , Hennessy Bryan , Green Marjorie , Buzdar Aman U. , Singletary S. Eva , Hortobagyi Gabriel N. , Pusztai Lajos
Published: September 2007

Purpose

To measure residual disease after neoadjuvant chemotherapy in order to improve the prognostic information that can be obtained from evaluating pathologic response.

Patients and Methods

Pathologic slides and reports were reviewed from 382 patients in two different treatment cohorts: sequential paclitaxel (T) then fluorouracil, doxorubicin, and cyclophosphamide (FAC) in 241 patients; and a single regimen of FAC in 141 patients. Residual cancer burden (RCB) was calculated as a continuous index combining pathologic measurements of primary tumor (size and cellularity) and nodal metastases (number and size) for prediction of distant relapse-free survival (DRFS) in multivariate Cox regression analyses.

Results

RCB was independently prognostic in a multivariate model that included age, pretreatment clinical stage, hormone receptor status, hormone therapy, and pathologic response (pathologic complete response [pCR] v residual disease [RD]; hazard ratio = 2.50; 95% CI 1.70 to 3.69; P < .001). Minimal RD (RCB-I) in 17% of patients carried the same prognosis as pCR (RCB-0). Extensive RD (RCB-III) in 13% of patients was associated with poor prognosis, regardless of hormone receptor status, adjuvant hormone therapy, or pathologic American Joint Committee on Cancer stage of residual disease. The generalizability of RCB for prognosis of distant relapse was confirmed in the FAC-treated validation cohort.

Conclusion

RCB determined from routine pathologic materials represented the distribution of RD, was a significant predictor of DRFS, and can be used to define categories of near-complete response and chemotherapy resistance.
Phase II Pethema Trial of Alternating Bortezomib and Dexamethasone As Induction Regimen Before Autologous Stem-Cell Transplantation in Younger Patients With Multiple Myeloma: Efficacy and Clinical Implications of Tumor Response Kinetics
Authors: Rosiñol Laura , Oriol Albert , Mateos Maria Victoria , Sureda Anna , García-Sánchez Pedro , Gutiérrez Norma , Alegre Adrián , Lahuerta Juan José , de la Rubia Javier , Herrero Carlos , Liu Xiangyang , Van de Velde Helgi , San Miguel Jesús , Bladé Joan
Published: September 2007

Purpose

This is the first study in which bortezomib and dexamethasone were administered on an alternating basis as up-front therapy in multiple myeloma (MM). We investigated the efficacy and kinetics of response to each drug and safety.

Patients and Methods

Patients with newly diagnosed MM who were less than 66 years old were treated with bortezomib at 1.3 mg/m2 on days 1, 4, 8, and 11 (cycles 1, 3, and 5) and dexamethasone 40 mg orally on days 1 through 4, 9 to 12, and 17 to 20 (cycles 2, 4, and 6), followed by autologous stem-cell transplantation (ASCT). Responses were evaluated by modified European Bone Marrow Transplantation criteria. Random effects models were used to analyze the tumor response kinetics.

Results

Forty patients were enrolled. Partial response (PR) or greater was 65% (12.5% complete response [CR], 10% very good PR [VGPR], and 42.5% PR) plus 17.5% minor response. Time to response was rapid, with 82% serum M-protein reduction achieved within the first two cycles. The M-protein decrease was similar with dexamethasone and with bortezomib (P = .48). Chromosome 13 deletion, t(4;14), and t(14;16) did not have a negative impact on response. Toxicity was low, with no grade 3 to 4 peripheral neuropathy and no grade 2 to 4 thrombocytopenia. The response rate after ASCT was 88%, with 33% CR (negative immunofixation) plus 22% VGPR.

Conclusion

Bortezomib alternating with dexamethasone is a highly effective induction regimen with low toxicity. The kinetic study has shown a high degree of heterogeneity in response and rapid effect from both agents, supporting the use of a short induction regimen before ASCT in MM.
Identification of a Polycystic Ovary Syndrome Susceptibility Variant in Fibrillin-3 and Association with a Metabolic Phenotype
Authors: Urbanek Margrit , Sam Susan , Legro Richard S. , Dunaif Andrea
Published: September 2007

Context: Polycystic ovary syndrome (PCOS), the most common reproductive endocrine disorder of premenopausal women, is also associated with metabolic abnormalities including insulin resistance and an increased risk for diabetes mellitus. We previously mapped a PCOS susceptibility locus to chromosome 19p13.2 near the dinucleotide repeat marker D19S884.

Objective: Our objective is to localize the chromosome 19p13.2 PCOS susceptibility locus and determine its impact on metabolic features of PCOS.

Design: Resequencing and family-based association testing were used to examine the effect of sequence variation within 100 kb of D19S884 on the reproductive and metabolic phenotypes of PCOS.

Setting: The study was conducted in an academic medical center.

Subjects: Genetic analyses were performed on DNA obtained from1723 individuals in 412 families with 412 index cases and 43 affected sisters of predominantly European origin (>94%). Genotype-phenotype associations were assessed in 601 women with PCOS and 168 brothers of affected women.

Results: D19S884 allele 8 (A8) within intron 55 of the fibrillin-3 (FBN3) gene showed the strongest evidence for association with PCOS of 53 variants tested (Pcorrected = 0.0037). A8 was also associated with higher levels of fasting insulin and homeostasis model assessment for insulin resistance in women with PCOS and higher fasting levels of proinsulin and proinsulin/insulin ratio in brothers.

Conclusions: These findings strongly suggest that A8 of D19S884 is the chromosome 19p13.2 PCOS susceptibility locus. The association of D19S884 with markers of insulin resistance and pancreatic β-cell dysfunction suggests that the same variant contributes to the reproductive and metabolic abnormalities of PCOS in affected women and their brothers.
The Endogenous Cannabinoid System Stimulates Glucose Uptake in Human Fat Cells via Phosphatidylinositol 3-Kinase and Calcium-Dependent Mechanisms
Authors: Pagano Claudio , Pilon Catia , Calcagno Alessandra , Urbanet Riccardo , Rossato Marco , Milan Gabriella , Bianchi Katiuscia , Rizzuto Rosario , Bernante Paolo , Federspil Giovanni , Vettor Roberto
Published: September 2007

Background: The endogenous cannabinoid system participates in the regulation of energy balance, and its dysregulation may be implicated in the pathogenesis of obesity. Adipose tissue endocannabinoids may produce metabolic and endocrine effects, but very few data are available in human adipose tissue and in primary human fat cells.

Experimental Design: We measured expression of type 1 and type 2 cannabinoid receptors (CNR), enzymes of cannabinoids synthesis and degradation in human omental, sc abdominal, and gluteal adipose tissue from lean and obese subjects. Furthermore, we assessed the effect of CNR1 stimulation on glucose uptake and intracellular transduction mechanisms in primary human adipocytes. Then we assessed the reciprocal regulation between CNR1 and peroxisome proliferator-activated receptor-γ (PPARγ). Finally, we tested whether leptin and adiponectin are regulated by CNR1 in human adipocytes.

Results: We found that most genes of the endocannabinoid system are down-regulated in gluteal fat and up-regulated in visceral and sc abdominal adipose tissue of obese patients. Treatment of adipocytes with rosiglitazone markedly down-regulated CNR1 expression, whereas Win 55,212 up-regulated PPARγ. Win 55,212 increased (+50%) glucose uptake, the translocation of glucose transporter 4, and intracellular calcium in fat cells. All these effects were inhibited by SR141716 and wortmannin and by removing extracellular calcium. Win 55,212 and SR141716 had no effect on expression of adiponectin and leptin.

Conclusions: These results indicate a role for the local endocannabinoids in the regulation of glucose metabolism in human adipocytes and suggest a role in channeling excess energy fuels to adipose tissue in obese humans.
Hypothalamic-Pituitary-Adrenal Axis Activity in Obese Men with and without Sleep Apnea: Effects of Continuous Positive Airway Pressure Therapy
Authors: Vgontzas A. N. , Pejovic S. , Zoumakis E. , Lin H.-M. , Bentley C. M. , Bixler E. O. , Sarrigiannidis A. , Basta M. , Chrousos G. P.
Published: September 2007

Context: Previous studies on the association between the hypothalamic-pituitary-adrenal axis activity and sleep apnea (SA) and obesity are inconsistent and/or limited.

Objective: In this study, we evaluated the activity of the hypothalamic-pituitary-adrenal axis in nonpsychologically distressed obese subjects with and without SA and examined the impact of continuous positive airway pressure (CPAP) in SA patients.

Design and Participants: In study I, four-night sleep laboratory recordings and serial 24-h plasma measures of cortisol were obtained in 45 obese men with and without apnea and nonobese controls. Sleep apneic patients were reassessed after 3 months of CPAP use. In study II, 38 obese men with and without sleep apnea and nonobese controls were challenged with ovine CRH administration after four nights in the sleep laboratory.

Results: The sleep patterns were similar between obese and nonobese controls. Twenty-four-hour plasma cortisol levels were highest in nonobese controls, intermediate in obese apneic patients, and lowest in obese controls (8.8 ± 0.4 vs. 8.1 ± 0.3 vs. 7.5 ± 0.3 μg/dl, P < 0.05). CPAP tended to reduce cortisol levels in the apneic patients (difference −0.7 ± .4 μg/dl, P = 0.1). CRH administration resulted in a higher ACTH response in both obese groups, compared with nonobese controls; the three groups were not different in cortisol response.

Conclusions: Nonpsychologically distressed, normally sleeping, obese men had low cortisol secretion. The cortisol secretion was slightly activated by SA and returned to low by CPAP use. The low cortisol secretion in obesity through its inferred hyposecretion of hypothalamic CRH might predispose the obese to sleep apnea.
Prolonged Reactive Oxygen Species Generation and Nuclear Factor-κB Activation after a High-Fat, High-Carbohydrate Meal in the Obese
Authors: Patel Chinmay , Ghanim Husam , Ravishankar Shreyas , Sia Chang Ling , Viswanathan Prabhakar , Mohanty Priya , Dandona Paresh
Published: September 2007

Background: Because obesity is associated with chronic oxidative and inflammatory stress, and high-fat, high-carbohydrate meals induce significant oxidative and inflammatory stress in normal subjects, we have now hypothesized that the intake of a high-fat, high-carbohydrate meal would result in a greater and more prolonged oxidative and inflammatory stress in the obese than in normal subjects.

Methods: Ten normal-weight and eight obese subjects were given a high-fat, high-carbohydrate meal after an overnight fast. Blood samples were collected at baseline and hourly following the meal for 3 h.

Results: Reactive oxygen species generation by mononuclear cells increased significantly by 2 h in both groups but continued to increase significantly at 3 h in the obese subjects, whereas in normal subjects it returned to baseline. Levels of p47phox increased significantly (by 81 ± 26%) at 3 h in obese individuals (P < 0.05), whereas there was no significant change in p47phox in normal subjects. Nuclear factor-κB DNA binding in mononuclear cells increased significantly (by 48 ± 58%, P < 0.036) at 2 h but not at 3 h in normal subjects, whereas in the obese, nuclear factor-κB increased significantly at both 2 and 3 h (by 36 ± 57 and 42 ± 63%, respectively, P < 0.004). Matrix metalloproteinase-9 concentrations were significantly higher in the obese at baseline (580 ± 103.9 vs. 373 ± 30.03 ng/ml, P < 0.05) and increased to significantly greater concentrations after the meal than in the lean subjects.

Conclusions: High-fat, high-carbohydrate meals induced a significantly more prolonged and greater oxidative and inflammatory stress in the obese. This may contribute to the increased atherogenic risk in obesity.
Association of BRAF V600E Mutation with Poor Clinicopathological Outcomes in 500 Consecutive Cases of Papillary Thyroid Carcinoma
Authors: Lupi Cristiana , Giannini Riccardo , Ugolini Clara , Proietti Agnese , Berti Piero , Minuto Michele , Materazzi Gabriele , Elisei Rossella , Santoro Massimo , Miccoli Paolo , Basolo Fulvio
Published: September 2007

Context: Because very few studies have examined the correlation between BRAF mutations and clinicopathological features of papillary thyroid carcinoma (PTC), we analyzed here a large and homogeneous cohort of patients with PTC for the presence of the BRAF mutation.

Objective: We examined BRAF mutations in a consecutive series of 500 PTC patients who underwent surgery in the Department of Surgery of the University of Pisa, and we correlated the presence of the mutation with clinicopathological parameters of the patients: age, gender, tumor size, presence of tumor capsule, extrathyroidal invasion, multicentricity, presence of node metastases, and tumor class.

Design: BRAF (exon 15) mutation was examined by PCR-single strand conformational polymorphism followed by DNA sequencing in laser-capture microdissected tissue samples.

Results: In this study, BRAF mutation was found in 219 of 500 cases (43.8%). In particular, we found the most common BRAF V600E mutation in 214 cases (42.8%), BRAF K601E mutation in three cases (0.6%), BRAF VK600–1E (0.2%) in one case, whereas in one case we found a new 14-bp deletion with concomitant 2-bp insertion, VKSR600–3del and T599I, respectively. BRAF V600E was associated with extrathyroidal invasion (P < 0.0001), multicentricity (P = 0.0026), presence of nodal metastases (P = 0.0009), class III vs. classes I and II (P < 0.00000006), and absence of tumor capsule (P < 0.0001), in particular in follicular- and micro-PTC variants. By multivariate analysis, the absence of tumor capsule remained the only parameter associated (P = 0.0005) with BRAF V600E mutation.

Conclusions: Our data suggest that BRAF V600E mutation is associated with high-risk PTC and in particular in follicular variant with invasive tumor growth.
Risk Factors for Development of Coronary Heart Disease in Patients with Acromegaly: A Five-Year Prospective Study
Authors: Bogazzi Fausto , Battolla Luigi , Spinelli Cheti , Rossi Giuseppe , Gavioli Silvia , Di Bello Vitantonio , Cosci Chiara , Sardella Chiara , Volterrani Duccio , Talini Enrica , Pepe Pasquale , Falaschi Fabio , Mariani Giuliano , Martino Enio
Published: September 2007

Background: Data on coronary heart disease (CHD) are scanty and matter of argument in acromegalic patients.

Objective: The objective of this study was to evaluate risk factors for development of CHD and the occurrence of cardiac events in acromegalic patients during a 5-yr prospective study.

Design: Ten-year likelihood for CHD development was estimated by the Framingham scoring system (FS); patients were stratified as having low (FS < 10), intermediate (≥ 10 FS < 20), or high (FS ≥ 20) risk. Coronary artery calcium content was measured using the Agatston score (AS) in all patients; those with positive AS were submitted to myocardial single-photon emission computed tomography; cardiac events were recorded during a 5-yr follow-up period.

Patients: Fifty-two consecutive patients (31 women, mean age 52 ± 11 yr) with controlled or uncontrolled acromegaly were followed prospectively for 5 yr.

Results: Thirty-seven patients (71%) had low, 14 patients (27%) had intermediate, and one patient (2%) had high CHD risk. CHD risk was unrelated to acromegaly activity or the estimated duration of disease. Among patients with FS less than 10%, 24 had AS equal to 0, eight had AS of 1 or greater and less than 100, and five had AS 100 or greater and less than 300, respectively. Among patients with FS 10 or greater and less than 20%, nine had AS equal to 0, two had AS of one or greater and less than 100, one had AS of 100 or greater and less than 300, and two had AS of 300 or greater; a patient of the latter group, having AS of 400 or greater, increased his CHD risk from 11% to 20% or more. FS or AS did not differ in patients with controlled or uncontrolled acromegaly (P = 0.981). All patients with positive AS had no single photon emission computed tomography perfusion defects. During the 5-yr follow-up period no patient developed ischemic cardiac events.

Conclusions: CHD risk in acromegalic patients, predicted by FS as in nonacromegalic subjects, is low; AS might have adjunctive role only in a subset of patients. However, most patients have systemic complications of acromegaly, which participate in the assessment of global CHD risk.
Speed as a stand-alone indicator of the quality of the railway track
Authors: Demiridis N , Pyrgidis C
Published: September 2007

A method for the assessment of the quality of the railway track is presented, introducing speed as a stand-alone quality indicator. Speed is expressed by means of the maximum permissible track speed VTR, max, which is considered to depend upon the satisfaction of a predefined set of safety, comfort, and reliability criteria. Calculations are performed by means of analytical models. The method can be applied to any railway network, regardless of technical or operational characteristics; it can assist infrastructure managers in their track maintenance management decision-making process. Extensions of the proposed method are feasible in order to include additional speed-related performance criteria, e.g. noise and vibrations.
Railway risk assessment - the fuzzy reasoning approach and fuzzy analytic hierarchy process approaches: A case study of shunting at Waterloo depot
Authors: An M , Huang S , Baker C J
Published: September 2007

Railway safety is a very complicated subject, which is determined by numerous aspects including human error. Many of the railway risk assessment techniques currently used are comparatively mature tools. However, in many circumstances, the application of these tools may not give satisfactory results because the risk data are incomplete or there is a high level of uncertainty involved in the risk data. This article presents a risk assessment methodology for conducting systematic risk assessment using fuzzy reasoning approach and fuzzy analytical hierarchy decision-making process. In this method, qualitative descriptors are employed to describe frequency of occurrence, consequence severity, weight factor, and risk level. The proposed risk assessment method can evaluate both qualitative and quantitative risk data, and information associated with railway operation efficiently and effectively. The outcomes of risk assessment are represented as the risk degrees and the defined risk categories of risk levels (RLs) with a belief of percentage, which provide very useful risk information to decision makers. This will provide railway risk analysts, managers, and engineers with a method and tool to improve their safety management and set safety standards. A case study of risk assessment of shunting at Waterloo depot is used to illustrate the application of the proposed methodology.
Effect of probability of detection upon the definition of inspection intervals for railway axles
Authors: Carboni M , Beretta S
Published: September 2007

The need to optimize inspection intervals of railway wheelsets involves, among other aspects, a reliable estimation of fatigue crack growth in the axles. With this in mind, the present paper focuses on the description of the considered axle made of A1N steel, and on some typical load spectra. Application of an opportune algorithm, derived from the dedicated soft-ware NASGRO®, made it possible to obtain life predictions in terms of cycles, and to discuss the influence of service loads. Life estimates were then analysed together with probability of detection curves of different non-destructive testing techniques in order to determine the total probability of observing, during periodical inspections, cracks or defects.
A model to predict the probability of highway rail crossing accidents
Authors: McCollister G M , Pflaum C C
Published: September 2007

In the current paper, a model to predict the probability of accidents, injuries, and fatalities resulting from collisions between trains and vehicles at highway rail crossings is presented. Logistic regression and two databases maintained by the US Federal Railroad Administration (FRA) are used to build the models. These models prove more than an order of magnitude more accurate than a previous model developed by the FRA, which is currently used to compute the cost effectiveness of crossing upgrades. A declining trend in the likelihood of an accident that cannot be explained by changes in crossings or highways over time is discovered. Possible causes of this trend and test one of these possibilities are discussed. The model is used to compute both the cost per life saved from upgrading each crossing without gates and the trend over time in the number of crossings that are cost effective to upgrade.
Machine vision analysis of the energy efficiency of intermodal freight trains
Authors: Lai Y-C , Barkan C P L , Drapa J , Ahuja N , Hart J M , Narayanan P J , Jawahar C V , Kumar A , Milhon L R , Stehly M P
Published: September 2007

Intermodal (IM) trains are typically the fastest freight trains operated in North America. The aerodynamic characteristics of many of these trains are often relatively poor resulting in high fuel consumption. However, considerable variation in fuel efficiency is possible depending on how the loads are placed on railcars in the train. Consequently, substantial potential fuel savings are possible if more attention is paid to the loading configuration of trains.

A wayside machine vision (MV) system was developed to automatically scan passing IM trains and assess their aerodynamic efficiency. MV algorithms are used to analyse these images, detect and measure gaps between loads. In order to make use of the data, a scoring system was developed based on two attributes - the aerodynamic coefficient and slot efficiency. The aerodynamic coefficient is calculated using the Aerodynamic Subroutine of the train energy model. Slot efficiency represents the difference between the actual and ideal loading configuration given the particular set of railcars in the train. This system can provide IM terminal managers feedback on loading performance for trains and be integrated into the software support systems used for loading assignment.
Impact of Drug Use and Comorbidities on In-Hospital Falls in Patients with Chronic Kidney Disease
Authors: Angalakuditi Mallik V , Gomes Joseph , Coley Kim C
Published: September 2007

Background:

In-hospital falls are a major problem in healthcare institutions and contribute to morbidity and mortality in this setting. Patients with chronic kidney disease (CKD) were previously found to be at higher risk for experiencing an in-hospital fall.

Objective:

To evaluate the association between comorbidities and drug use with the risk of in-hospital falls in adults with CKD.

Methods:

A retrospective case-control study was conducted in patients with CKD hospitalized between January 1, 1998, and June 30, 2003. Cases included patients who experienced an in-hospital fait, were 18 years of age or older, and had been hospitalized for more than 24 hours. For every case, 2 controls were identified and matched for CKD, age, and sex. Information about comorbidities and drug use was collected from an electronic medical data repository. Statistical tests performed were t-tests, χ2 analysis, and multivariate logistic regression, using occurrence of a fall as the dependent variable and race, comorbidities, and drug groups as covariates.

Results:

There were 635 fall cases that met study criteria. The mean age of patients was 68 ± 15 years, 54% were female, and 82% were white. There were 1270 matched controls with CKD who were included in the regression analysis. Comorbidities that increased the likelihood of experiencing an in-hospital fall were dementia (OR 2.63), pneumonia (OR 1.72), gastrointestinal disease (OR 1.41), and diabetes (OR 1.31). Drugs associated with an in-hospital fall were antidepressants (OR 1.65) and anticonvulsants (OR 1.52).

Conclusions:

Several comorbidities, especially dementia, significantly increase the risk of experiencing an in-hospital fall in patients with CKD. Drugs that place CKD patients at risk include antidepressants and anticonvulsants.
Risk of Treatment-Emergent Diabetes Mellitus in Patients Receiving Antipsychotics
Authors: Citrome Leslie L , Holt Richard IG , Zachry Woodie M , Clewell Jerry D , Orth Paul A , Karagianis Jamie L , Hoffmann Vicki Poole
Published: September 2007

Background:

Type 2 diabetes mellitus has been reported during antipsychotic treatment.

Objective:

To quantify the potential risk of treatment-emergent diabetes mellitus among patients receiving antipsychotic medications.

Methods:

The MEDLINE and Psychinfo databases were searched using the key words antipsychotic (including individual drug names), diabetes, risk, and incidence for all English-language articles published between 1966 and 2005. Risk calculations were performed using data obtained from pharmacoepidemiologic studies that met the following criteria: (1) cohort design, (2) determination of preexisting diabetes, (3) inclusion of antipsychotic monotherapy as an exposure variable, and (4) comparison with exposure to first-generation antipsychotics. Studies meeting these criteria were used to calculate incidence, attributable risk between agents, and number needed to harm.

Results:

A total of 25 observational pharmacoepidemiologic studies were found comparing antipsychotics on the outcome of diabetes mellitus. Sufficient information was provided in 15 of the reports to be able to estimate attributable risk, Attributable risk for individual second-generation antipsychotics relative to first-generation antipsychotics ranged from 53 more to 46 fewer new cases of diabetes per 1000 patients. Little observable difference was noted between the individual second-generation antipsychotics versus first-generation antipsychotics on this outcome. However, few of the studies controlled for body weight, race or ethnicity, or the presence of diabetogenic medications. None adjusted for familial history of diabetes, levels of physical activity, or diet, as this information is not usually available in the databases used in pharmacoepidemiologic studies.

Conclusions:

Based on the published pharmacoepidemiologic reports reviewed, the avoidance of diabetes as an outcome cannot be predictably achieved with precision by choice of a second- versus a first-generation antipsychotic. Risk management for new-onset diabetes requires the assessment of established risk factors such as family history, advancing age, non-white ethnicity, diet, central obesity, and level of physical activity.
Potential Interactions Between Complementary/Alternative Products and Conventional Medicines in a Medicare Population
Authors: Elmer Gary W , Lafferty William E , Tyree Patrick T , Lind Bonnie K
Published: September 2007

Background:

Despite the high prevalence of complementary and alternative medicine (CAM) product use among the elderly, little is known about the extent of concurrent CAM-conventional medicine use and the potential for adverse reactions.

Objective:

To determine the prevalence of CAM product use concurrent with conventional medications, prescription and nonprescription, in a Medicare population and assess the risk for adverse interactions.

Methods:

Retrospective analysis was performed on Cardiovascular Health Study interview data from 1994, 1995, 1997, and 1999. The prevalence of concurrent combinations of CAM products and conventional drugs was tabulated. The adverse interaction risks were categorized as unknown, theoretical, and significant.

Results:

Of 5052 participants, the median age was 75, 60.2% were female, 16.6% were African American, and 83.4% were white. The percent using CAM products during the 4 time periods was 6.3%, 6.7%, 12.8%, and 15.1 %, The percent using both CAM products and conventional drugs was 6.0%. 6.2%. 11.7%, and 14.4%, Of these, 294 (5.8%) individuals took combinations considered to have a significant risk for an adverse interaction. Combinations with risk were observed on 393 separate interviews. Most (379) involved a risk of bleeding due to use of ginkgo, garlic, or ginseng together with aspirin, warfarin, ticlopidine, or pentoxifylline. An additional 786 observations of combinations were considered to have some, albeit theoretical or uncertain, risk (or an adverse interaction.

Conclusions:

Concurrent use of CAM products and conventional medicines in a Medicare population was found to be common. Research to define the risks of combining ginkgo and garlic supplements with aspirin should be of high priority.
Weighing In: Emergent Diabetes Mellitus and Second-Generation Antipsychotics
Authors: Dufresne Robert L
Published: September 2007

Of all the metabolic effects of some of the atypical second-generation antipsychotics, their potential to induce glucose dysregulation has induced a storm of controversy over the past several years. The numerous published epidemiologic studies are difficult to interpret due to the high background rate of type 2 diabetes mellitus in this population, the inherent problems with analysis of observational data, and the short duration of the available studies. A plan to monitor for weight gain, hypertriglyceridemia, glucose dysregulation, and other potential adverse metabolic effects resulting from antipsychotic treatment is critical.
Grain Growth in Nanocrystalline Metal Thin Films under In Situ Ion-Beam Irradiation
Authors: Kaoumi D. , Motta A. T. , Birtcher R. C.
Published: September 2007

In-situ observations in a transmission electron microscope (TEM) were used to study the microstructure evolution in metal Zr, Pt, Cu, and Au nanocrystalline thin films under ion-beam irradiation. Free-standing films were prepared by sputter deposition. Samples were irradiated in-situ at the Intermediate Voltage Electron Microscope (IVEM) at Argonne National Laboratory with Ar and Kr ions to fluences in excess of 1016 ion/cm2. As a result of irradiation, grain growth was observed in all samples using Bright Field (BF) imaging in the TEM. The average grain size increased monotonically with ion fluence until it reached a saturation value. Similarly to thermal grain growth, the ion-irradiation induced grain growth curves could be best fitted with curves of the type: Dn-D0n=KΦ. The irradiations were done at temperatures ranging from 20 to 773 K. The results suggest the existence of three regimes with respect to irradiating temperature: (i) a purely thermal regime, which appears to start above the bulk coarse-grained recrystallization temperature, (ii) a thermally assisted regime where thermal diffusion and irradiation effects combine to increase the rate of grain growth relative to that resulting from either of these mechanisms alone, and (iii) an athermal regime (low-temperature regime) where irradiation can by itself cause grain growth. The transition temperature between the athermal regime and the thermally assisted regime depends on the material, but is in the range 0.14–0.22 times the melting point. The influence of the ion type was also investigated on Zr-Fe irradiated with 600 keV Kr ions versus 600 keV Ar ions.
Nuclear Factor-κB Activation via Tyrosine Phosphorylation of Inhibitor κB-α Is Crucial for Ciliary Neurotrophic Factor-Promoted Neurite Growth from Developing Neurons
Authors: Gallagher Denis , Gutierrez Humberto , Gavalda Nuria , O'Keeffe Gerard , Hay Ron , Davies Alun M.
Published: September 2007

The cytokine ciliary neurotrophic factor (CNTF) promotes the growth of neural processes from many kinds of neurons in the developing and regenerating adult nervous system, but the intracellular signaling mechanisms mediating this important function of CNTF are poorly understood. Here, we show that CNTF activates the nuclear factor-κB (NF-κB) transcriptional system in neonatal sensory neurons and that blocking NF-κB-dependent transcription inhibits CNTF-promoted neurite growth. Selectively blocking NF-κB activation by the noncanonical pathway that requires tyrosine phosphorylation of inhibitor κB-α (IκB-α), but not by the canonical pathway that requires serine phosphorylation of IκB-α, also effectively inhibits CNTF-promoted neurite growth. CNTF treatment activates spleen tyrosine kinase (SYK) whose substrates include IκB-α. CNTF-induced SYK phosphorylation is rapidly followed by increased tyrosine phosphorylation of IκB-α, and blocking SYK activation or tyrosine phosphorylation of IκB-α prevents CNTF-induced NF-κB activation and CNTF-promoted neurite growth. These findings demonstrate that NF-κB signaling by an unusual activation mechanism is essential for the ability of CNTF to promote the growth of neural processes in the developing nervous system.