bluuebunny/crossref_metadata_2025 huggingface dataset:
Impaired Expression of Peripheral Blood Apoptotic‐Related Gene Transcripts in Acute Multiple Sclerosis Relapse
Authors: ACHIRON ANAT , FELDMAN ANNA , MANDEL MATHILDA , GUREVICH MICHAEL
Published: September 2007

Abstract:  Differential expression of apoptotic genes may influence the susceptibility of activated lymphocytes to expand and induce acute relapse and persistent inflammation in patients with relapsing–remitting multiple sclerosis (RRMS). The exact relationship between alterations in apoptotic‐related gene expression and clinical disease activity has not been broadly evaluated. In this study we studied peripheral blood mononuclear cells (PBMCs) expression of pro‐ and antiapoptotic genes in RRMS patients during acute relapse in comparison to patients in remission. Using cDNA Affymetrix microarrays platform (U133A2 microarrays) we analyzed the gene expression profile of PBMC derived from 22 RRMS patients in acute relapse (15 females, mean age 34.6 ± 1.8 years, disease duration 5.6 ± 0.8 years) in comparison to 20 sex‐ and age‐matched RRMS patients in remission. One thousand five hundred seventy‐eight gene transcripts significantly differentiated acute multiple sclerosis (MS) relapse from remission. This characteristic gene expression signature was enriched by an apoptotic‐related pathway. The 1578 gene transcripts that significantly differentiated acute relapse from remission were enriched by 55 apoptotic‐related genes in that reflected different operating pathways during the acute phase of the disease. These genes mainly involved the caspase‐dependent pathway and included overexpression of the negative regulator of FAS‐induced apoptosis (TOSO) and the BCL2 antiapoptotic family members (BCL2, BCL2 AA) as well as downexpression of proapoptotic genes like BAX, apoptotic protease‐activating factor 1 (APAF1) and caspases 1, 2, 8, 9. and 10. An additional group of antiapoptotic genes related to T cell receptor‐mediated apoptosis was also found to be overexpressed in acute relapse and included TCR‐binding CD3E antigen, antiapoptotic serine threonin kinase (AKT), and NFκB‐associated genes like reticuloendotheliosis viral oncogene homolog A (RELA) and human T cell leukemia virus type I‐binding protein (Tax1BP) known to inhibit tumor necrosis factor (TNF)‐induced apoptosis. Our findings demonstrate impaired apoptotic mechanisms in peripheral lymphocytes from RRMS patients during acute relapse. This suggests that the inflammatory process in active disease is targeted by inhibition of proapoptotic and repression of antiapoptotic genes that allow prolonged abnormal immune responses.
Antibodies to the Lens and Cornea in Anti‐DFS70‐Positive Subjects
Authors: BIZZARO NICOLA , TONUTTI ELIO , VISENTINI DANIELA , ALESSIO MARIA GRAZIA , PLATZGUMMER STEFAN , MOROZZI GABRIELLA , ANTICO ANTONIO , VILLALTA DANILO , PILLER‐RONER SONIA , VIGEVANI ENRICO
Published: September 2007

Abstract:  Autoantibodies against DFS70 (dense fine speckles 70) antigen have recently been identified among antinuclear antibodies (ANA) in patients with various inflammatory diseases and in patients with different types of cancer. These antibodies are recognized using indirect immunofluorescence (IIF) on HEp‐2 cells, by a fine speckled nuclear staining in interphase HEp‐2 cells and a positive reaction in the chromosome region of mitotic cells. Given that the DFS70 protein is also known as the lens epithelium‐derived growth factor, this study was performed with two objectives: (a) to assess the prevalence of these antibodies in patients sent for ANA testing and in 334 patients with different types of neoplasia and (b) to determine whether the lens tissue was a suitable substrate for the detection of antibodies specific to lens proteins. During routine workup for ANA detection by the IIF method, we found 172 DFS70‐positive sera among 21,516 consecutive samples (prevalence, 0.8%). In the group of patients with neoplastic disease, 6 of 334 (1.8%) were anti‐DFS70‐positive. DFS70‐positive sera were then assayed by the IIF method on cryostatic sections of mouse eye at a dilution of 1:40 with an anti‐human IgG conjugate. Among the 172 DFS70‐positive samples detected by the ANA screening, 32 (19%) were strongly reactive against the reticular fibers of the lens; 8 (5%) were positive only to the corneal epithelium (nuclear negative); 5 (3%) were positive both for the cornea and the lens fibers; 13 (7%) stained only the nuclei of lens and cornea cells, and 4 (2%) were positive against the ciliary muscle. Among the patients with neoplastic diseases, only one with lung cancer reacted weakly with the reticular fibers of the lens. Sera from 20 healthy blood donors were negative. In this preliminary study, we have shown that the prevalence of anti‐DFS70 antibodies is much lower than previously reported, both in patients screened for ANA and in patients with cancer. We have also seen that some DFS70‐positive sera have antibodies that recognize antigens of the lens. Further studies are needed to investigate the fine specificity and the possible significance of these new autoantibodies.
Is the c‐Cbl Proto‐Oncogene Involved in Chronic Lymphocytic Leukemia?
Authors: MANKAÏ AMANI , EVEILLARD JEAN‐RICHARD , BUHÉ VIRGINIE , LE STER KARINE , LOISEL SÉVERINE , GHEDIRA IBTISSEM , YOUINOU PIERRE , BERTHOU CHRISTIAN , BORDRON ANNE
Published: September 2007

Abstract:  Chronic lymphocytic leukemia (CLL) is characterized by survival advantage and accumulation of CD5+ mature B lymphocytes. Expression of zeta‐chain‐associated protein‐70 (ZAP‐70), normally present in T lymphocytes or immature B cells, is associated with disease aggressiveness, as IgVH mutational status, and some proteins implicated in survival signal pathways are found to be constitutively activated in CLL cells. ZAP‐70 signaling is regulated through molecular adaptors, such as the proto‐oncogene product c‐Casitas B lineage lymphoma (c‐Cbl). The aim of this study was to determine the implication of this proto‐oncogene product in CLL in survival signals. It appeared that expression of c‐Cbl was increased in CLL and not correlated to that of B cell linker protein or ZAP‐70. Furthermore, c‐Cbl was significantly hypophosphorylated in progressive disease, so that hypophosphorylated form of c‐Cbl (c‐Cbl.P) along with ZAP‐70, set a cutoff ratio distributing patients with stable situation below 1, and those with progressive disease equal or above 1. Given that phospholipase gamma 2 (PLCγ2) function is also influenced by c‐Cbl hypophosphorylation, the ratio of PLCγ2 to c‐Cbl.P was measured in CLL B cells and consistently found to be ≥ 1 in Binet stage B CLL patients, as opposed to stage A CLL patients. These findings invite analysis of the role of c‐Cbl in CLL.
Autoantibodies in Patients with Monoclonal Gammopathies
Authors: CARLIZZI GUGLIELMO , CIARLA MARIA VERA , DI LUZIO ANDREA , LABRIOLA RAFFAELLA , FRATTOLILLO DANIELE , SPIRIDIGLIOZZI PATRIK , MASALA CESARE , STROM ROBERTO
Published: September 2007

Abstract: Although autoantibody activities are rather often associated to monoclonal gammopathies, only monoclonal immunoglobulins of the IgM isotype are really directed against autoantigens that are often polysaccharides or are formed by highly repetitive structures. This strict association is frequently revealed also by clinical manifestations of the autoimmune response generated by the monoclonal macroglobulin. Most monoclonal immunoglobulins of non‐IgM isotype are instead totally inactive toward self‐antigens, the autoantibody activity being instead associated, if present, to polyclonal immunoglobulins. Although the same BAFF/APRIL system is involved in perpetuation of humoral autoimmunity as well as in stimulation of clonal B‐cell expansion, the autoimmune commitment of B cells of a non‐IgM isotype is hardly compatible with their possible involvement in an uncontrolled proliferation pathway, whose prerequisite is the homing of these B cells to the bone marrow compartment. The IgM‐secreting cells appear instead to possess a much lower tendency, and/or a looser requirement, for their homing in the bone marrow prior to their actual proliferation. This may explain the quite different consequences, in terms of autoimmunity, between IgM and non‐IgM paraproteinemias.
The Clinical Significance of IgA Antimitochondrial Antibodies in Sera and Saliva in Primary Biliary Cirrhosis
Authors: TANAKA ATSUSHI , NEZU SAEKO , UEGAKI SATOKO , MIKAMI MASAKI , OKUYAMA SHUHEI , KAWAMURA NAOHIRO , AISO MITSUHIKO , GERSHWIN M. ERIC , TAKAHASHI SHIN‐ICHI , SELMI CARLO , TAKIKAWA HAJIME
Published: September 2007

Abstract:  It still remains unclear how antimitochondrial autoantibodies (AMA) are involved with immunopathogenesis of primary biliary cirrhosis (PBC). We have suggested the potential role of IgA‐AMA in damage to epithelial cells in PBC. In the current study, we investigated whether IgA‐AMA were detectable in sera and saliva of PBC patients, to examine the association between detectable IgA‐type autoantibodies in sera or saliva and progression of liver diseases. Fifty‐three patients with PBC were enrolled, and IgA‐AMA in sera and saliva were sought by immunoblotting using pork heart mitochondria as antigens. The progression of PBC was determined as Scheuer's classification consisting of four histological stages. We found IgA‐AMA, IgA‐anti‐PDC‐E2, and IgA‐anti‐E3BP in 43/53 (81%), 37/53 (70%), and 35/53 (66%) sera of patients with PBC, but none of controls. The progression of PBC was statistically associated with presence of IgA‐anti‐PDC‐E2 (P= 0.0124), but neither with IgA‐AMA (P= 0.1296) nor anti‐IgA‐E3BP (P= 0.5973). In saliva, detectable IgA‐AMA, IgA‐anti‐PDC‐E2, and IgA‐anti‐E3BP were noted in 12/26 (46%), 6/26 (23%), and 11/26 (42%), respectively. Detection of IgA‐anti‐PDC‐E2 was strongly associated with progression of PBC (P= 0.0002), whereas detection of IgA‐AMA and IgA‐anti‐E3BP were not associated (P= 0.2145 and P= 0.5118). The current findings suggest that the presence of IgA‐anti‐PDC‐E2 in sera or saliva might be associated with progression of PBC, although a prospective study with PBC patients with detectable IgA‐anti‐PDC‐E2 at early stages will be required to conclude the contribution of IgA‐anti‐PDC‐E2 to the progression of PBC.
Decrease in Binding for the Neuropeptide VIP in Response to Marked Inflammation of the Mucosa in Ulcerative Colitis
Authors: JÖNSSON MARIA , NORRGÅRD ÖRJAN , HANSSON MAGNUS , FORSGREN STURE
Published: September 2007

Abstract:  The neuropeptide vasoactive intestinal peptide (VIP) is involved in the neuroimmunomodulation of the intestine. In the present study, specimens from the sigmoid colon of ulcerative colitis (UC) and non‐UC patients were examined for immunohistochemistry and in vitro receptor autoradiography. Marked occurrence of VIP binding was observed in the mucosa. However, there were very low levels of binding in areas showing pronounced inflammation/derangement. The study shows that marked derangement of the mucosa leads to a distinct decrease in VIP binding. Thus, it is possible that a decrease in trophic and anti‐inflammatory VIP effects occurs in areas exhibiting a very marked inflammation.
Gluten Ataxia
Authors: BOSCOLO SABRINA , SARICH ALESSANDRA , LORENZON ANDREA , PASSONI MONICA , RUI VERONICA , STEBEL MARCO , SBLATTERO DANIELE , MARZARI ROBERTO , HADJIVASSILIOU MARIOS , TONGIORGI ENRICO
Published: September 2007

Abstract:  Gluten sensitivity is an autoimmune disease that usually causes intestinal atrophy resulting in a malabsorption syndrome known as celiac disease. However, gluten sensitivity may involve several organs and is often associated with extraintestinal manifestations. Typically, patients with celiac disease have circulating anti‐tissue transglutaminase and anti‐gliadin antibodies. When patients with gluten sensitivity are affected by other autoimmune diseases, other autoantibodies may arise like anti‐epidermal transglutaminase in dermatitis herpetiformis, anti‐thyroid peroxidase antibodies in thyroiditis, and anti‐islet cells antibodies in type 1 diabetes. The most common neurological manifestation of gluten sensitivity is ataxia, the so‐called gluten ataxia (GA). In patients with GA we have demonstrated that anti‐gliadin and anti‐tissue transglutaminase antibodies cross‐react with neurons but that additional anti‐neural antibodies are present. The aim of the present article is to review the knowledge on animal models of gluten sensitivity, as well as reviewing the role of anti‐neural antibodies in GA.
Randomized Controlled Trial of Yoga Among a Multiethnic Sample of Breast Cancer Patients: Effects on Quality of Life
Authors: Moadel Alyson B. , Shah Chirag , Wylie-Rosett Judith , Harris Melanie S. , Patel Sapana R. , Hall Charles B. , Sparano Joseph A.
Published: September 2007

Purpose

This study examines the impact of yoga, including physical poses, breathing, and meditation exercises, on quality of life (QOL), fatigue, distressed mood, and spiritual well-being among a multiethnic sample of breast cancer patients.

Patients and Methods

One hundred twenty-eight patients (42% African American, 31% Hispanic) recruited from an urban cancer center were randomly assigned (2:1 ratio) to a 12-week yoga intervention (n = 84) or a 12-week waitlist control group (n = 44). Changes in QOL (eg, Functional Assessment of Cancer Therapy) from before random assignment (T1) to the 3-month follow-up (T3) were examined; predictors of adherence were also assessed. Nearly half of all patients were receiving medical treatment.

Results

Regression analyses indicated that the control group had a greater decrease in social well-being compared with the intervention group after controlling for baseline social well-being and covariates (P < .0001). Secondary analyses of 71 patients not receiving chemotherapy during the intervention period indicated favorable outcomes for the intervention group compared with the control group in overall QOL (P < .008), emotional well-being (P < .015), social well-being (P < .004), spiritual well-being (P < .009), and distressed mood (P < .031). Sixty-nine percent of intervention participants attended classes (mean number of classes attended by active class participants = 7.00 ± 3.80), with lower adherence associated with increased fatigue (P < .001), radiotherapy (P < .0001), younger age (P < .008), and no antiestrogen therapy (P < .02).

Conclusion

Despite limited adherence, this intent-to-treat analysis suggests that yoga is associated with beneficial effects on social functioning among a medically diverse sample of breast cancer survivors. Among patients not receiving chemotherapy, yoga appears to enhance emotional well-being and mood and may serve to buffer deterioration in both overall and specific domains of QOL.
Effects of Aerobic and Resistance Exercise in Breast Cancer Patients Receiving Adjuvant Chemotherapy: A Multicenter Randomized Controlled Trial
Authors: Courneya Kerry S. , Segal Roanne J. , Mackey John R. , Gelmon Karen , Reid Robert D. , Friedenreich Christine M. , Ladha Aliya B. , Proulx Caroline , Vallance Jeffrey K.H. , Lane Kirstin , Yasui Yutaka , McKenzie Donald C.
Published: September 2007

Purpose

Breast cancer chemotherapy may cause unfavorable changes in physical functioning, body composition, psychosocial functioning, and quality of life (QOL). We evaluated the relative merits of aerobic and resistance exercise in blunting these effects.

Patients and Methods

We conducted a multicenter randomized controlled trial in Canada between 2003 and 2005 that randomly assigned 242 breast cancer patients initiating adjuvant chemotherapy to usual care (n = 82), supervised resistance exercise (n = 82), or supervised aerobic exercise (n = 78) for the duration of their chemotherapy (median, 17 weeks; 95% CI, 9 to 24 weeks). Our primary end point was cancer-specific QOL assessed by the Functional Assessment of Cancer Therapy–Anemia scale. Secondary end points were fatigue, psychosocial functioning, physical fitness, body composition, chemotherapy completion rate, and lymphedema.

Results

The follow-up assessment rate for our primary end point was 92.1%, and adherence to the supervised exercise was 70.2%. Unadjusted and adjusted mixed-model analyses indicated that aerobic exercise was superior to usual care for improving self-esteem (P = .015), aerobic fitness (P = .006), and percent body fat (adjusted P = .076). Resistance exercise was superior to usual care for improving self-esteem (P = .018), muscular strength (P < .001), lean body mass (P = .015), and chemotherapy completion rate (P = .033). Changes in cancer-specific QOL, fatigue, depression, and anxiety favored the exercise groups but did not reach statistical significance. Exercise did not cause lymphedema or adverse events.

Conclusion

Neither aerobic nor resistance exercise significantly improved cancer-specific QOL in breast cancer patients receiving chemotherapy, but they did improve self-esteem, physical fitness, body composition, and chemotherapy completion rate without causing lymphedema or significant adverse events.
Relationship Between Epidemiologic Risk Factors and Breast Cancer Recurrence
Authors: Brewster Abenaa M. , Do Kim-Anh , Thompson Patricia A. , Hahn Karin M. , Sahin Aysegul A. , Cao Yumei , Stewart Maureen M. , Murray James L. , Hortobagyi Gabriel N. , Bondy Melissa L.
Published: September 2007

Purpose

Early-stage breast cancers are biologically heterogeneous and vary in clinical behavior, supporting the role of factors other than tumor size and lymph node involvement as outcome determinants. We evaluated the effect of epidemiologic breast cancer risk factors on recurrence in women with early-stage disease.

Patients and Methods

Medical records from 2,327 women with early-stage breast cancer, treated at the M.D. Anderson Cancer Center between 1985 and 2000, were used to derive information on epidemiologic, clinical, and histological factors. Cox proportional hazards models were used to estimate the hazard ratios of 5-year risk of breast cancer recurrence adjusted for treatment and stage. Statistical tests were two-sided.

Results

None of the breast cancer risk factors were associated with recurrence, adjusting for tumor characteristics and treatment. A significant interaction between hormone replacement therapy (HRT) use and tumor hormone receptor status on risk of recurrence (P = .0003) was observed. Among ever-users of HRT, recurrence risk was two-fold lower for estrogen receptor (ER) –positive and progesterone receptor (PR) –positive tumors compared with ER- and PR-negative tumors; whereas, among never-users of HRT, there was no statistically significant association between recurrence risk and receptor status.

Conclusion

HRT users who develop receptor-positive early-stage disease have better outcomes than those who develop receptor-negative disease. Among never-users of HRT, the expected beneficial effect of ER- or PR-positive tumors on recurrence risk was absent. These data lend support to the notion that the biology of hormone receptor–positive disease in HRT users differs from that in nonusers.
Randomized Active-Controlled Phase II Study of Denosumab Efficacy and Safety in Patients With Breast Cancer-Related Bone Metastases
Authors: Lipton Allan , Steger Guenther G. , Figueroa Jazmin , Alvarado Cristina , Solal-Celigny Philippe , Body Jean-Jacques , de Boer Richard , Berardi Rossana , Gascon Pere , Tonkin Katia S. , Coleman Robert , Paterson Alexander H.G. , Peterson Mark C. , Fan Michelle , Kinsey Amy , Jun Susie
Published: September 2007

Purpose

Denosumab, a fully human monoclonal antibody to receptor activator of nuclear factor-κB ligand, suppresses bone resorption. In this study, we evaluated the efficacy and safety of five dosing regimens of denosumab in patients with breast cancer-related bone metastases not previously treated with intravenous bisphosphonates (IV BPs).

Patients and Methods

Eligible women (n = 255) with breast cancer-related bone metastases were stratified by type of antineoplastic therapy received and randomly assigned to one of six cohorts (five denosumab cohorts [blinded to dose and frequency]; one open-label IV BP cohort). Denosumab was administered subcutaneously every 4 weeks (30, 120, or 180 mg) or every 12 weeks (60 or 180 mg). The primary end point was percentage of change in the bone turnover marker urine N-telopeptide corrected for urine creatinine (uNTx/Cr) from baseline to study week 13. The percentage of patients achieving more than 65% uNTx/Cr reduction, time to more than 65% uNTx/Cr reduction, patients experiencing one or more on-study skeletal-related events (SRE), and safety were also evaluated.

Results

At study week 13, the median percent reduction in uNTx/Cr was 71% for the pooled denosumab groups and 79% for the IV BP group. Overall, 74% of denosumab-treated patients (157 of 211) achieved a more than 65% reduction in uNTx/Cr compared with 63% of bisphosphonate-treated patients (27 of 43). On-study SREs were experienced by 9% of denosumab-treated patients (20 of 211) versus 16% of bisphosphonate-treated patients (seven of 43). No serious or fatal adverse events related to denosumab occurred.

Conclusion

Subcutaneous denosumab may be similar to IV BPs in suppressing bone turnover and reducing SRE risk. The safety profile was consistent with an advanced breast cancer population receiving systemic therapy.
Melphalan, Prednisone, and Lenalidomide Treatment for Newly Diagnosed Myeloma: A Report From the GIMEMA—Italian Multiple Myeloma Network
Authors: Palumbo Antonio , Falco Patrizia , Corradini Paolo , Falcone Antonietta , Di Raimondo Francesco , Giuliani Nicola , Crippa Claudia , Ciccone Giovannino , Omedè Paola , Ambrosini Maria Teresa , Gay Francesca , Bringhen Sara , Musto Pellegrino , Foà Robin , Knight Robert , Zeldis Jerome B. , Boccadoro Mario , Petrucci Maria Teresa
Published: September 2007

Purpose

Lenalidomide has shown significant antimyeloma activity in clinical studies. Oral melphalan, prednisone, and thalidomide have been regarded as the standard of care in elderly multiple myeloma patients. We assessed dosing, efficacy, and safety of melphalan, prednisone, and lenalidomide (MPR) in newly diagnosed elderly myeloma patients.

Patients and Methods

Oral melphalan was administered in doses ranging from 0.18 to 0.25 mg/kg on days 1 to 4, prednisone at a 2-mg/kg dose on days 1 to 4, and lenalidomide at doses ranging from 5 to 10 mg on days 1 to 21, every 28 days for nine cycles, followed by maintenance therapy with lenalidomide alone. Aspirin was given as a prophylaxis for thrombosis.

Results

Fifty-four patients were enrolled and evaluated after completing the assigned treatment schedule. The maximum tolerated dose was defined as 0.18 mg/kg melphalan and 10 mg lenalidomide. With these doses, 81% of patients achieved at least a partial response, 47.6% achieved a very good partial response, and 23.8% achieved a complete immunofixation-negative response. In all patients, 1-year event-free and overall survival rates were 92% and 100%, respectively. At the maximum tolerated dose, grade 3 adverse events included neutropenia (38.1%), thrombocytopenia (14.2%), febrile neutropenia (9.5%), vasculitis (9.5%), and thromboembolism (4.8%); grade 4 adverse events were neutropenia (14.2%) and thrombocytopenia (9.5%).

Conclusion

Oral MPR therapy is a promising first-line treatment for elderly myeloma patients. Hematologic adverse events were frequent but manageable. A low incidence of nonhematologic adverse events was noted. Aspirin appears to provide adequate antithrombosis prophylaxis.
Bone Mineral Density in Adults with the Metabolic Syndrome: Analysis in a Population-Based U.S. Sample
Authors: Kinjo Mitsuyo , Setoguchi Soko , Solomon Daniel H.
Published: September 2007

Background: The metabolic syndrome is associated with low-grade inflammation. It has been suggested that proinflammatory cytokines and low-grade systemic inflammation activate bone resorption and may lead to reduced bone mineral density (BMD), but no previous studies have evaluated the association between the metabolic syndrome and BMD. We examined this relationship in a representative U.S. population-based sample from the Third National Health and Nutrition Examination Survey (NHANES III, 1988–1994).

Methods: We identified adult subjects enrolled in NHANES III with the metabolic syndrome as defined by the criteria of the Adult Treatment Panel III. We conducted a cross-sectional analysis of femoral neck BMD (FN-BMD) for subjects with and without the metabolic syndrome. Analyses were adjusted for relevant covariates and stratified by quintile of body mass index.

Results: Among 8197 persons at least 20 yr old who underwent FN-BMD measurement, 1773 (22%) had the metabolic syndrome. After multivariable adjustment, FN-BMD was higher among subjects with the metabolic syndrome (0.86 g/cm2) than those without (0.80 g/cm2; P < 0.0001). When stratified by body mass index, FN-BMD was similar between subjects with and without the metabolic syndrome. Adjusted FN-BMD increased with additional components of the metabolic syndrome (P < 0.0001 for trend), and there was a significant positive association with abdominal obesity (P < 0.0001). A subgroup of subjects with diabetes had higher FM-BMD than those without, independent of abdominal obesity.

Conclusions: In NHANES III, the metabolic syndrome was not associated with reduced FN-BMD.
An analytical model for the natural frequencies of a railway wheel and comparison with experimental results
Authors: Sakamoto H
Published: September 2007

Vibration generated at the contact surface between rails and wheels have been considered the main cause of noise from railway vehicles. Such noises are classified into three types: rolling, impact, and squeal noises. The mechanisms by which each noise is generated have been well researched.

The current study treats mainly lateral and vertical vibrations of railway wheels, and focuses on squeal noises that originate on curves. The current study includes calculations of the natural frequencies of wheels based on elasticity theory, laboratory tests to measure the natural frequencies of wheels, and field tests to measure the sounds and vibrations of railway wheels. Many researchers have calculated natural frequencies by the finite-element method, which can give the exact quantitative number when information such as the model and boundary conditions is correct. The author obtained frequencies by elasticity theory, because a qualitative understanding is thought necessary, regardless of the boundary condition.

The results of the current study showed that the origin of the squeal noise on a curved track comes from the lateral vibration of the wheel; but it is shown that the dominant component of rolling noise on a straight track at around 800 Hz is not related to wheel vibration.
A multi-layer model of low adhesion between railway wheel and rail
Authors: Olofsson U
Published: September 2007

The current paper presents a new multi-layer model of low adhesion between railway wheel and rail. The model proposes that when leaves are crushed between railway wheels and rail, both a coated slippery layer and a chemically reacted, easily sheared surface layer are formed. Elemental depth profiling reveals that the chemically reacted, easily sheared surface layer contains substances such as P and Ca. Both the coated slippery layer and the chemically reacted, easily sheared surface layer must be removed to get proper adhesion between railway wheel and rail.
Effect of suspension system in the lateral stability of railway freight trucks
Authors: Molatefi H , Hecht M , Kadivar M H
Published: September 2007

In the current research an empty freight wagon with BA652 and an old BA661 bogies have been modelled. Non-linear creep forces with spin moment between wheel and rail have been used and also all impacts and friction forces have been modelled. The characteristics of primary suspension systems for BA652 and an old BA661 have been evaluated by means of test. Non-linear equations of motions and kinematical constraints have been solved in time domain and limit cycles have been showed. Both primary and secondary hunting can be seen in responses of wagon. For BA652 there are non-linear and linear critical speeds and also saddle nodes but for old BA661 the situation is too critical and the system can oscillate in very low speeds.
Dynamic adhesion model and adaptive sliding mode brake control system for the railway rolling stocks
Authors: Choi J J , Park S H , Kim J S
Published: September 2007

Main factor of the braking mechanism for the railway rolling stocks is the adhesion force which is a friction force occurred between rail and wheel. Mathematically, the adhesion force is a function of the slip ratio which is a relative velocity between the rail and wheel, and its magnitude depends on the condition of the rail surface and axle load. Although, the adhesion force affects considerably the performance of the traction and the braking of the rolling stocks, it is impossible to measure it in the real time. Huge amount of attention is given to the modelling of adhesion force. However, the previous proposed models show only the static relation between slip ratio and adhesion force that is induced by experimental experiences. In the current paper, novel dynamic model of the adhesion force is proposed under the assumption that the wheel slip is regarded as the irregular contact between the wheel and rail surface. Based on this proposed adhesion force model, the brake control system is designed using adaptive sliding mode control scheme to realize robust antislip brake control. In the controller design process, the running resistance and unmodelled system dynamics are considered as system uncertainty, and the weight of rolling stocks is represented as changeable parameter and adaptive law is induced using Lyapunov stability theorem. The performance of the proposed antislip brake control system using novel adhesion force model is evaluated by the computer simulation.
Analysis of the structural characteristics of an intermediate rail vehicle and their effect on vehicle crash performance
Authors: Xue X , Schmid F , Smith R A
Published: September 2007

In the current paper, the authors present an analysis of the structural characteristics of an intermediate rail vehicle and their effects on crash performance of the vehicle. Theirs is a simulation based analysis involving four stages. First, the crashworthiness of the vehicle is assessed by simulating an impact of the vehicle with a rigid wall. Second, the structural characteristics of the vehicle are analysed based on the structural behaviour during this impact and then the structure is modified. Third, the modified vehicle is tested again in the same impact scenario with a rigid wall. Finally, the modified vehicle is subjected to a modelled head-on impact which mirrors the real-life impact interface between two intermediate vehicles in a train impact.

The emphasis of the current study is on the structural characteristics of the intermediate vehicle and the differences compared to an impact of a leading vehicle. The study shows that, similar to a leading vehicle, bending, or jackknifing is a main form of failure in this conventionally designed intermediate vehicle. It has also been found that the location of the door openings creates a major difference in the behaviour of an intermediate vehicle. It causes instability of the vehicle in the door area and leads to high stresses at the joint of the end beam with the solebar and shear stresses at the joint of the inner pillar with the cantrail. Apart from this, the shapes of the vehicle ends and impact interfaces are also different and have an effect on the crash performance of the vehicles. The simulation results allow the identification of the structural characteristics and show the effectiveness of relevant modifications. The conclusions have general relevance for the crashworthiness of rail vehicle design.
A simple method to determine train running resistance from full-scale measurements
Authors: Lukaszewicz P
Published: September 2007

This article proposes a simple method to determine train running resistance. The resistance is determined by calculating the change in kinetic and potential energy of a coasting train between successive measurement positions. The strength of this method is that the measuring equipment needed is kept at a minimum and it is not limited to a track having a constant grade, thus making this method suitable, in particular, for long freight trains running in mountain areas. An error analysis is performed for this method and the probable error sources are discussed.
Fingolimod: A Novel Immunosuppressant for Multiple Sclerosis
Authors: Brown Brandon A , Kantesaria Pranish P , McDevitt Lisa M
Published: September 2007

Objective:

To review the pharmacology, pharmacokinetics, efficacy, and safety of fingolimod, a novel immune modulator.

Data Sources:

Information was obtained through a MEDLINE search (1966–February 2007) and from published abstracts. Search terms included fingolimod, FTY720, FTY-720, and sphlngosine-1-phosphate receptor agonist.

Study Selection and Data Extraction:

All English-language studies and abstracts pertaining to fingolimod were considered for inclusion. Preference was given to human data.

Data Synthesis:

Fingolimod Is the first in a new class of immune modulators known as the sphingosine-1-phosphate receptor agonists. It is administered orally once dairy and causes a dose-related reduction in the number ot circulating lymphocytes by preventing their egress from secondary lymph organs, but it does not alter T-cell activation or proliferation. Bradycardia and lymphopenia are the most common adverse effects. Clinical trials have evaluated the efficacy of fingolimod in renal transplantation and multiple sclerosis (MS). Further research for renal transplantation will not take place, but Phase 3 studies in MS are underway, as Phase 2 study results are favorable.

Conclusions:

Due to its distinct mechanism of action and its oral administration, fingolimod may be a useful therapeutic option for patients with relapsing forms of MS. More data are needed to assess the safety and clinical utility of fingolimod.
LInezolid for the Treatment of Nocardia spp. Infections
Authors: Jodlowski Tomasz Z , Melnychuk Igor , Conry John
Published: September 2007

Objective:

To review the available evidence regarding the use of linezolid for the treatment of Nocardia spp. infections.

Data Sources:

Data were identified through a search of MEDLINE (1966-May 2007), American Search Premier (1975-May 2007), International Pharmaceutical Abstracts (1960-2007), Science Citation Index Expanded (1996-2007), and Cochrane Databases (publications archived until May 2007) using the terms linezolid and Nocardia.

Study Selection and Data Extraction:

Prospective and retrospective studies, case reports, case series, and in vitro studies were eligible for inclusion if they used linezolid for nocardiosis regardless of site of infection and outcome.

Data Synthesis:

We identified 11 published cases of linezolid use for Nocardia spp. infections. The predominant species isolated were N. asteroides (n=4; 36%) and N. farcinica (n= 3; 27%). Nocardiosis with central nervous system involvement (n= 7; 64%) or disseminated disease (n= 4; 36%) were most common. The main reason for discontinuation of previous antimicrobials was most often related to adverse effects (n= 5; 45%), followed by clinical failure (n = 3; 27%). Linezolid was associated with cure or improvement in all cases (n =11; 100%). However, the majority of patients developed serious complications that may have led to premature discontinuation of therapy with linezolid, including myelosuppression (n = 5; 45%) or possible/confirmed peripheral neuropathy (n = 2; 18%).

Conclusions:

The limited published data suggest that linezolid appears to be an effective alternative to trimethoprim/sulfamethoxazole for the treatment of nocardiosis. Unfortunately, the high cost and potentially serious long-term toxicities of linezolid appear to limit its use and relegate it to salvage therapy alone or in combination with other antimicrobials.
Frequency of Adverse Events Associated with Intravenous Immunoglobulin Therapy in Patients with Pemphigus or Pemphigoid
Authors: Gürcan Hakan M , Ahmed A Razzaque
Published: September 2007

Background:

Intravenous immunoglobulin (IVIG) therapy is widely used in immune-mediated diseases as an immunomodulatory agent and is considered to be a safe biologic agent.

Objective:

To determine the frequency of adverse events associated with IVIG therapy in patients with pemphigus and pemphigoid.

Methods:

We retrospectively reviewed data on patients treated with IVIG for pemphigus and pemphigoid over a 10 year period. Patients had pemphigus vulgaris, pemphigus foliaceus, mucous membrane pemphigoid, or bullous pemphigoid. IVIG was given according to a published protocol at a dose of 2 g/kg administered over 3–5 days at prescribed intervals. Patient records were reviewed for information on sex, age, duration of treatment, number of cycles given, number of days each patient received IVIG, weight of each patient, IVIG dose each patient received per infusion, and early or delayed adverse effects reported by patients or observed by healthcare providers.

Results:

We identified 9892 infusions given to 174 patients. Headaches were the most common adverse effects; they were observed during 886 (8.9%) infusions and involved 123 (70.6%) patients. The incidence of other minor adverse effects, including fatigue, nausea, vomiting, chills, urticaria, swollen glands, hoarseness, thoracic discomfort, and palpitations, was 0.57–3.4% per infusion and 0.04–1,3% per patient. Hoarseness of voice and swelling of cervical lymph nodes have not been previously reported. Acute renal failure occurred in one patient and was the only major adverse effect observed. None of the patients required hospitalization, and there were no deaths.

Conclusions:

Adverse events associated with IVIG therapy are usually mild and self-limiting. The incidence of serious adverse events is low. Identification of risk factors and close monitoring of high-risk patients throughout the therapy are likely to decrease the occurrence of rare serious and less likely fatal adverse effects.
Long-Term Continuation on Cardiovascular Drug Treatment in Patients with Coronary Heart Disease
Authors: Wald David S , Morton Geraint , Walker Kate , Losson Neil , Curzen Nick P
Published: September 2007

Background:

Combination therapy to reduce risk factors is effective in preventing recurrent cardiovascular disease events in patients with coronary heart disease (CHD), but medications need to be continued indefinitely to maximize the benefits.

Objective:

To evaluate the extent of long-term continuation with cardiovascular drug therapy and its expected impact on the prevention of CHD.

Methods:

We studied 242 patients with CHD who underwent percutaneous coronary intervention following an acute coronary syndrome over a 6 month period in 2004. We prospectively examined the extent to which specific drugs and drug combinations were continued over lime by reviewing medication use at the time of hospital discharge and after 2 years. The results were used to estimate the expected loss in preventive efficacy due to discontinuation of therapy.

Results:

The changes over a 2 year period in the proportions of patients taking each drug class were as follows: 15% reduction for aspirin (95% Cl, -21 to -9), 10% reduction for statins (95% Cl, -16 to 5), 19% reduction for angiotensin-converting enzyme inhibitors (95% Cl, -26 to -12), 12% reduction for β-blockers (95% Cl, -18 to -6), 0% increase for calcium-channel blockers (95% Cl, -5 to 6), 2% increase for thiazides (95% Cl, -2 to 6), and 12% increase for angiotensin-11 receptor blockers (95% Cl, 6 to 18). The combination of aspirin, statin, and at least 2 blood pressure lowering drugs was prescribed to 81% of patients, three-quarters of whom remained on this combination after 2 years. The overall expected preventive effect on CHD of the combined medication taken during hospitalization and after 2 years was 80% and 74%, respectively.

Conclusions:

In patients with CHD, long-term continuation of combination cardiovascular drug therapy is considerably greater than generally perceived.
Activation of theWnt–βCatenin Pathway in a Cell Population on the Surface of the Forebrain Is Essential for the Establishment of Olfactory Axon Connections
Authors: Zaghetto Ambra A. , Paina Sara , Mantero Stefano , Platonova Natalia , Peretto Paolo , Bovetti Serena , Puche Adam , Piccolo Stefano , Merlo Giorgio R.
Published: September 2007

A variety of signals governing early extension, guidance, and connectivity of olfactory receptor neuron (ORN) axons has been identified; however, little is known about axon–mesoderm and forebrain (FB)–mesoderm signals. UsingWnt–βcatenin reporter mice, we identify a novel Wnt-responsive resident cell population, located in aFrizzled7expression domain at the surface of the embryonic FB, along the trajectory of incoming ORN axons. Organotypic slice cultures that recapitulate olfactory-associated Wnt–βcatenin activation show that the βcatenin response depends on a placode-derived signal(s). Likewise, inDlx5−/− embryos, in which the primary connections fail to form,Wnt–βcatenin response on the surface of the FB is strongly reduced. The olfactory placode expresses a number of βcatenin-activating Wnt genes, and theFrizzled7receptor transduces the “canonical” Wnt signal; using Wnt expression plasmids we show that Wnt5a and Wnt7b are sufficient to rescue βcatenin activation in the absence of incoming axons. Finally, blocking the canonical Wnt pathway with the exogenous application of the antagonists Dikkopf-1 or secreted-Frizzled-receptor protein-2 prevents ORN axon contact to the FB. These data reveal a novel function for Wnt signaling in the establishment of periphery–CNS olfactory connections and highlight a complex interplay between cells of different embryonic origin for ORN axon connectivity.
Multimodal Coding of Three-Dimensional Rotation and Translation in Area MSTd: Comparison of Visual and Vestibular Selectivity
Authors: Takahashi Katsumasa , Gu Yong , May Paul J. , Newlands Shawn D. , DeAngelis Gregory C. , Angelaki Dora E.
Published: September 2007

Recent studies have shown that most neurons in the dorsal medial superior temporal area (MSTd) signal the direction of self-translation (i.e., heading) in response to both optic flow and inertial motion. Much less is currently known about the response properties of MSTd neurons during self-rotation. We have characterized the three-dimensional tuning of MSTd neurons while monkeys passively fixated a central, head-fixed target. Rotational stimuli were either presented using a motion platform or simulated visually using optic flow. Nearly all MSTd cells were significantly tuned for the direction of rotation in the absence of optic flow, with more neurons preferring roll than pitch or yaw rotations. The preferred rotation axis in response to optic flow was generally the opposite of that during physical rotation. This result differs sharply from our findings for translational motion, where approximately half of MSTd neurons have congruent visual and vestibular preferences. By testing a subset of neurons with combined visual and vestibular stimulation, we also show that the contributions of visual and vestibular cues to MSTd responses depend on the relative reliabilities of the two stimulus modalities. Previous studies of MSTd responses to motion in darkness have assumed a vestibular origin for the activity observed. We have directly verified this assumption by recording from MSTd neurons after bilateral labyrinthectomy. Selectivity for physical rotation and translation stimuli was eliminated after labyrinthectomy, whereas selectivity to optic flow was unaffected. Overall, the lack of MSTd neurons with congruent rotation tuning for visual and vestibular stimuli suggests that MSTd does not integrate these signals to produce a robust perception of self-rotation. Vestibular rotation signals in MSTd may instead be used to compensate for the confounding effects of rotatory head movements on optic flow.
Axonal Neurofilaments Control Multiple Fiber Properties But Do Not Influence Structure or Spacing of Nodes of Ranvier
Authors: Perrot Rodolphe , Lonchampt Pierre , Peterson Alan C. , Eyer Joël
Published: September 2007

In the vertebrate nervous system, axon calibers correlate positively with myelin sheath dimensions and electrophysiological parameters including action potential amplitude and conduction velocity. Neurofilaments, a prominent component of the neuronal cytoskeleton, are required by axons to support their normal radial growth. To distinguish between fiber features that arise in response to absolute axon caliber and those that are under autonomous control, we investigated transgenic mice in which neurofilaments are sequestered in neuronal cell bodies. The neurofilament deficient axons in such mice achieve mature calibers only 50% of normal and have altered conduction properties. We show here that this primary axonal defect also induces multiple changes in myelin sheath composition and radial dimensions. Remarkably, other fundamental fiber features, including internodal spacing and the architecture and composition of nodes of Ranvier, remain unaltered. Thus, many fiber characteristics are controlled through mechanisms operating independently of absolute axon caliber and the neurofilament cytoskeleton.
Synaptic Kainate Receptors Tune Oriens-Lacunosum Moleculare Interneurons to Operate at Theta Frequency
Authors: Goldin Miri , Epsztein Jérôme , Jorquera Isabel , Represa Alfonso , Ben-Ari Yehezkel , Crépel Valérie , Cossart Rosa
Published: September 2007

GABAergic interneurons of the hippocampus play an important role in the generation of behaviorally relevant network oscillations. Among this heterogeneous neuronal population, somatostatin (SOM)-positive oriens-lacunosum moleculare (O-LM) interneurons are remarkable because they are tuned to operate at theta frequencies (6–10 Hz)in vitroandin vivo. Recent studies show that a high proportion of glutamatergic synapses that impinge on O-LM interneurons are mediated by kainate receptors (KA-Rs). In the present study, we thus tested the hypothesis that KA-Rs transmit afferent inputs in O-LM neurons during synaptic stimulation at theta frequency. We combined multibeam two-photon calcium imaging in hippocampal slices from SOM–enhanced green fluorescent protein (EGFP) mice, to record the activity of SOM cells as well as hundreds of neurons simultaneously, and targeted electrophysiological recordings and morphological analysis to describe the morphofunctional features of particular cells. We report that EGFP-positive O-LM neurons are the only subtype of interneuron that reliably follows synaptic stimulation of the alveus in the theta frequency range. Electrophysiological recordings revealed the crucial contribution of KA-Rs to the firing activity and to the glutamatergic response to theta stimuli in O-LM cells compared with other cell types. The reliable activation of O-LM cells in the theta frequency range did not simply result from the longer kinetics of KA-R-mediated postsynaptic events (EPSPKA) but presumably from a specific interaction between EPSPKAand their intrinsic active membrane properties. Such preferential processing of excitatory inputs via KA-Rs by distally projecting GABAergic microcircuits could provide a key role in theta band frequency oscillations.