bluuebunny/crossref_metadata_2025 huggingface dataset:
Neutrophil elastase inducesIL-8gene transcription and protein release through p38/NF-κB activation via EGFR transactivation in a lung epithelial cell line
Authors: Kuwahara Ippei , Lillehoj Erik P. , Lu Wenju , Singh Ishwar S. , Isohama Yoichiro , Miyata Takeshi , Kim K. Chul
Published: April 2006

In this study, we investigated the regulation and mechanism of IL-8 expression by A549 human lung carcinoma cells treated with neutrophil elastase (NE). NE-treated cells exhibited significantly higher IL-8 protein levels in culture media compared with cells treated with vehicle alone. Blocking of gene transcription with actinomycin D suggested that NE stimulated IL-8 synthesis via increased mRNA expression, which was verified by real-time RT-PCR. NE activated the IL-8 promoter but did not alter the stability of its mRNA, confirming that the protease induced IL-8 synthesis through increased gene transcription. The results from the use of chemical inhibitors and mutant gene constructs against various signal transduction components seem to suggest the linear signaling pathway involving the activation of PKC-δ → dual oxidase 1 → reactive oxygen species → TNF-α-converting enzyme → EGF receptor → p38 → NF-κB for NE-activated IL-8 gene expression. A NF-κB potential binding site, located between nucleotides −82 and −69 of the IL-8 promoter, was identified as necessary for NE-induced IL-8 transcription. We conclude that NE increases IL-8 transcription through p38/NF-κB activation via EGFR transactivation.
Empirical modelling of the isothermal transformation of pearlite in hypereutectoid steel
Authors: Elwazri A. M. , Wanjara P. , Yue S.
Published: April 2006

The rate controlling mechanism for pearlite growth in a hypereutectoid steel composition was examined through an analysis of the microstructural characteristics of the pearlite structure, namely interlamellar spacing, for different isothermal transformation and austenitising conditions. From a metallographic analysis of the pearlite structure as a function of the austenitisation and undercooling conditions applied to the hypereutectoid steel, the interlamellar spacing was observed to increase with increasing austenitising temperature and increasing isothermal transformation temperature. Through the application and experimental validation of a theoretical model (Zener and Hillert) for the calculation of the pearlite interlamellar spacing as a function of the undercooling, the growth rate of pearlite in the hypereutectoid steel was determined to be controlled by the volume diffusion of carbon in austenite during isothermal transformation in the temperature range of 550–620°C.
Technique for direct measurement of effective fatigue threshold of materials
Authors: Narasaiah N. , Tarafder S. , Ray K. K.
Published: April 2006

A new method for studying crack growth behaviour in the fatigue threshold regime is reported here. The method uses a simple rotating bending test set-up, instead of servohydraulic or electromagnetic resonance test systems, to determine the fatigue threshold of structural materials. The reliability of the new technique is demonstrated by determining fatigue threshold of a 0·62%C steel by this technique and comparing the results with those obtained from conventional tests following the procedure of ASTM standard E647. The suggested technique provides higher sensitivity of measurement for crack growth rate and directly gives the fatigue threshold value for the steel that is in good agreement with the effective fatigue threshold determined by conventional tests.
Ultrasound Markers for Down's Syndrome—Dr Jekyll or Mr Hyde
Authors: Wyldes Mike
Published: April 2006

In this personal commentary, Mike Wyldes, Director of Midlands Ultrasound and Medical Services (MUMS) Ltd and Consultant Obstetrician and Gynaecologist at Birmingham Heartlands & Solihull Hospital, charts his personal feelings and experiences relating to the recognition of ultrasound 'soft markers' for Trisomy 21. He explains the rationale underpinning development and implementation of the recommendations of the West Midlands Regional Ultrasound Group and publication of their booklet Soft Markers—a Guide for Professionals.
Effect of pulsed Nd:YAG laser melting treatment on microstructural and corrosion behaviour of AZ91C Mg alloy
Authors: Padmavathi C. , Sundar J. K. Sarin , Joshi S. V. , Prasad Rao K.
Published: April 2006

In the present study, an attempt was made to improve the corrosion resistance and microhardness of a cast magnesium–aluminium–zinc alloy by laser surface melting. A 400 W pulsed Nd:YAG laser was used to melt and rapidly quench the surface of the cast AZ91C alloy to improve the corrosion resistance. This was evaluated using potentiodynamic polarisation and EIS studies. The microstructure of the melt pool was examined using optical microscopy and scanning electron microscopy (SEM) along with energy dispersive spectroscopy (EDS), X-ray diffraction studies (XRD) and X-ray fluorescence (XRF). The work revealed that laser melting improves the corrosion resistance of as cast AZ91C alloy because of its fine microstructure and extensive solubility of aluminium in eutectic ( β phase). The microhardness of the laser surface melted layer was also increased from 74 HV to 99–124 HV.
Quantitative characterisation of correlations between casting defects and mechanical strength of Al–7Si–Mg alloy castings
Authors: Yang X. , Huang X. , Dai X. , Campbell J. , Grant R. J.
Published: April 2006

An Omniment3 Instrument image analyser has been used for quantitative characterisation of casting defects. The concepts of the casting defect density and area fraction were proposed for the first time to quantify the effect of casting defects on the strength properties of castings. To complement the quantitative metallography, a conventional three point bend strength, i.e. ultimate bend strength (UBS), test was also conducted on specimens using three different runners. SEM was then applied for microstructure observation on the fracture section of the three point bend test specimens. In order to reveal the correlations between strength properties and casting defect density/area fraction in the specimens, the correlation coefficients are defined. Based on the quantitative characterisation of casting defects and strength test results, it is confirmed that there exist strong correlations between the strength properties of castings and the casting defect porosity. A correlation coefficient with a value close to 1 indicates that casting defect distribution across the castings is more uniform with fewer concentrated defects and higher correlation coefficients characterise more reliable castings. However, it is stressed that the final strength properties of the castings are not only manifested by the density and area fraction of casting defects but also influenced by the defect distribution features and the defect morphology. Concentrated casting distribution of defects such as shrinkage pores and casting defects with a sharp shape will generate stress concentration and damage the strength properties. Among the castings made using three different runner types, it was found that a casting defect distribution present in a casting plate made using a vortex flow runner (VR) was more uniform than those in casting plates made using rectangular runner (RR) and triangular runners (TR).
Diffusion at Cu/Sn interface during sintering process
Authors: Sánchez F. , Bolarín A. M. , Tello A. , Hernández L. E. , Bas J. A.
Published: April 2006

Thermal analysis and metallographic studies were used to describe two aspects of the sintering process of Cu–Sn alloys: (a) the microstructural changes at the Cu/Sn interface and (b) the direction of the diffusion between the elements. Cylindrical couples of copper and tin were used (4.5 × 10−3 m in diameter). The couples were sintered in a 20H2–80N2 atmosphere at temperatures of 573, 723, 923, 1058 and 1073 K and periods of time ranging from 1·2 to 7·2 ks. The heat treated couples were metallographically evaluated with electronic and optical microscopy. Differential thermal analysis (DTA) was carried out under the same experimental conditions to explain the diffusion process during the particle bonding. The results show that different reactions and phases formed during the thermal process, also, it was observed that the diffusion of copper into melted tin predominates during heating, and that the melted tin ( T>505 K) reacts with copper to form a new solid phase. A diffusion mechanism for mixtures of Cu–XSn powders is proposed.
Constitutive model development and hot extrusion simulation for AZ61 magnesium alloy
Authors: Zhou H. T. , Liu C. M. , Chen M. A.
Published: April 2006

Compression tests for the AZ61 magnesium alloy have been carried out at temperatures ranging from 200 to 400°C and with different strain rates from 10−3 to 5 s−1. The flow stress–strain curves show that the flow stress reaches a peak value and then decreases to a steady value. This steady value decreases with rising temperature and decreasing strain rate. A new constitutive model is developed to describe flow stress as a function of temperature T, strain rate ϵ, strain ϵ, and strain softening coefficient which is introduced into the simulation (final element method) of hot bar extrusion. The simulation results show that stress is relatively high around the entrance of the conical die, while the highest temperature and the largest strain appear near the exit of conical die. By comparing the simulation and experiment result, successful extrusion temperature and speed are 300°C and 10 mm s−1 respectively.
Anaerobic Digestion of Thermo‐Oxidized Excess Municipal Sludge
Authors: Cacho Rivero Jesús A. , Suidan Makram T.
Published: April 2006

The effect of a thermo‐oxidative co‐treatment placed between the two reactors of two‐stage anaerobic digestion of excess municipal sludge was studied. The oxidant used was hydrogen peroxide (H2O2), and moderate temperatures below the boiling point of water were considered. The first experiment was to elucidate the effect of two different temperatures (65 and 90°C) of oxidation using a constant oxidant dose of 1.0 g H2O2/g influent volatile suspended solids (VSSinfluent). The use of thermo‐oxidative co‐treatment increased overall solids destruction by 24.9 and 33.5%, respectively, when operating at 65 and 90°C, respectively. Because of this significant effect of temperature on the performance of the process, a second experiment was conducted using the higher temperature of 90°C while decreasing the hydrogen peroxide dosage to 0.5, 0.25, and 0.1 g H2O2/g VSSinfluent. An increase in solids destruction of 13.9, 18.9, and 25.6% was observed when the thermo‐oxidative co‐treatment was used using oxidant dosages of 0.1, 0.25, and 0.5 g H2O2/g VSSinfluent, respectively.
The International Law of Terrorist Financing
Authors: Bantekas Ilias
Published: April 2006

The international dimensions of terrorism had been identified prior to World War II. Nonetheless, no agreement could be reached on an acceptable definition, or appropriate action, and the 1937 Convention on the Prevention and Punishment of Terrorism, adopted by the League of Nations, was ratified by a single country. The issue resurfaced in the late 1950s when private individuals perpetrated an alarming number of incidents endangering civil aviation during transnational flights. These incidents led to the adoption of three distinct conventions on the subject, namely the 1963 Tokyo Convention on Offenses and Certain Other Acts Committed on Board Aircraft, the 1970 Hague Convention for the Suppression of Unlawful Seizure of Aircraft, and the 1971 Montreal Convention for the Suppression of Unlawful Acts Against the Safety of Civil Aviation.
Controlling the Use of Force: A Role for Human Rights Norms in Contemporary Armed Conflict
Authors: Watkin Kenneth
Published: April 2006

According to protesters, U.S. soldiers fired on them without provocation, killing seventeen people and wounding more than seventy. According to die U.S. military, the soldiers returned precision fire on gunmen in the crowd who were shooting at them.

—Human Rights Watch

The twenty-first century has witnessed significant challenges to the traditional view that international humanitarian law exclusively regulates the use of force in armed conflict. The death and destruction caused on September 11,2001, reflect the increasingly complex nature of modern conflict. Groups that rely on the benefits of globalization and technological advances to conduct operations across international borders are threatening the maintenance of international order. Their tools of violence range from conventional weapons of war to more modern weapons of mass destruction and potentially asymmetric “cyber attacks.”
Self-Defense and the Israeli Wall Advisory Opinion: An Ipse Dixit from the ICJ?
Authors: Murphy Sean D.
Published: April 2006

In October 2003, the Israeli permanent representative addressed the United Nations General Assembly on why Israel felt compelled to build a lengthy barrier spanning hundreds of kilometers across certain areas of the occupied West Bank of the Jordan River. Among other things, Ambassador Dan Gillernian stated:

[A] security fence has proven itself to be one of the most effective non-violent methods lor preventing terrorism in the heart of civilian areas. The fence is a measure wholly consistent with the right of States to self-defence enshrined in Article 51 of the Charter. International law and Security Council resolutions, including resolutions 1368 (2001) and 1373 (2001), have clearly recognized the right of States to use force in self-defence against terrorist attacks, and therefore surely recognize the right to use non-forcible measures to that end.
Words my Mother Never Taught Me—“In Defense of the International Court”
Authors: Scobbie Iain
Published: April 2006

Israel has justified the construction of its barrier wall as a nonforcible measure taken in selfdefense to protect its citizens against terrorist attacks emanating from the occupied Palestinian territory. This essay addresses two issues. First, was the International Court of Justice’s conclusion in paragraph 139 of the advisory opinionLegal Consequences of the Construction of a Wall in the Occupied Palestinian Territorythat “Article 51 of the Charter has no relevance in this case” wellfounded? This question involves consideration of three interrelated substantive aspects of paragraph 139: the Court’s finding that Article 51 was irrelevant because Israel did not claim that the attacks against it were imputable to a foreign state; the relevance of the Court’s reliance on the fact that Israel exercises control over the occupied Palestinian territory; and the Court’s conclusion that the situation differs from the circumstances contemplated in Security Council Resolutions 1368 (2001) and 1373 (2001) and that, accordingly, Israel could not invoke these resolutions in support of its claim to be exercising a right of self-defense. The second issue is whether the approach of the Court to the substantive content of Article 51 can be defended as an appropriate discharge of its judicial function. To avoid undue suspense, let it be said at the outset that paragraph 139 is well-founded, and the Court properly fulfilled its task.
Critical Reflections on the International Humanitarian Law Aspects of the ICJ Wall Advisory Opinion
Authors: Imseis Ardi
Published: April 2006

I shall confine my brief thoughts on the recent advisory opinion of the International Court of Justice (ICJ) on the legal consequences of the construction of a wall in the occupied Palestinian territory (OPT) to the Court’s treatment of international humanitarian law (IHL) in general, and to the law of belligerent occupation in particular. To that end, I will focus on the following four areas: the Court’s consideration of the applicable law as regards IHL; the Court’s interpretation of Article 6 of the 1949 Geneva Convention Relative to the Protection of Civilian Persons in Time of War; the Court’s consideration of the concept of military necessity in the context of foreign military occupation; and the Court’s consideration of the responsibility of third states, particularly the high contracting parties to the Fourth Geneva Convention, for violations of relevant principles of IHL by an occupying power.
Rapamycin and Interleukin-10 Treatment Induces T Regulatory Type 1 Cells That Mediate Antigen-Specific Transplantation Tolerance
Authors: Battaglia Manuela , Stabilini Angela , Draghici Elena , Gregori Silvia , Mocchetti Cristina , Bonifacio Ezio , Roncarolo Maria-Grazia
Published: April 2006

Islet transplantation is a cure for type 1 diabetes, but its potential is limited by the need for constant immunosuppression. One solution to this problem is the induction of transplantation tolerance mediated by T regulatory cells. T regulatory type 1 (Tr1) cells are characterized by their production of high levels of interleukin (IL)-10, which is crucial for their differentiation and suppressive function. We investigated the effects of IL-10 administered in combination with rapamycin on the induction of Tr1 cells that could mediate a state of tolerance in diabetic mice after pancreatic islet transplantation. The efficacy of this treatment was compared with IL-10 alone and standard immunosuppression. Stable long-term tolerance that was not reversible by alloantigen rechallenge was achieved only in mice treated with rapamycin plus IL-10. Tr1 cells that produced high levels of IL-10 and suppressed T-cell proliferation were isolated from splenocytes of rapamycin plus IL-10–treated mice after treatment withdrawal. In rapamycin plus IL-10–treated mice, endogenous IL-10 mediated an active state of tolerance, as was observed when the blockade of IL-10 activity rapidly induced graft rejection >100 days after transplantation. CD4+ T-cells from rapamycin plus IL-10–treated mice transferred antigen-specific tolerance in mice that received new transplants. Thus rapamycin plus IL-10 not only prevented allograft rejection but also induced Tr1 cells that mediated stable antigen-specific, long-term tolerance in vivo.
Glucosamine-Induced Endoplasmic Reticulum Dysfunction Is Associated With Accelerated Atherosclerosis in a Hyperglycemic Mouse Model
Authors: Werstuck Geoff H. , Khan Mohammad I. , Femia Giuseppe , Kim Anna J. , Tedesco Vivienne , Trigatti Bernardo , Shi Yuanyuan
Published: April 2006

Diabetes is a major independent risk factor for cardiovascular disease and stroke; however, the molecular and cellular mechanisms by which diabetes contributes to the development of vascular disease are not fully understood. Our previous studies demonstrated that endoplasmic reticulum (ER) stress–inducing agents, including homocysteine, promote lipid accumulation and activate inflammatory pathways—the hallmark features of atherosclerosis. We hypothesize that the accumulation of intracellular glucosamine observed in diabetes may also promote atherogenesis via a mechanism that involves ER stress. In support of this theory, we demonstrate that glucosamine can induce ER stress in cell types relevant to the development of atherosclerosis, including human aortic smooth muscle cells, monocytes, and hepatocytes. Furthermore, we show that glucosamine-induced ER stress dysregulates lipid metabolism, leading to the accumulation of cholesterol in cultured cells. To examine the relevance of the ER stress pathway in vivo, we used a streptozotocin-induced hyperglycemic apolipoprotein E–deficient mouse model of atherosclerosis. Using molecular biological and histological techniques, we show that hyperglycemia is associated with tissue-specific ER stress, hepatic steatosis, and accelerated atherosclerosis. This novel mechanism may not only explain how diabetes and hyperglycemia promote atherosclerosis, but also provide a potential new target for therapeutic intervention.
Adiponectin Does Not Cross the Blood-Brain Barrier but Modifies Cytokine Expression of Brain Endothelial Cells
Authors: Spranger Joachim , Verma Sulekha , Göhring Isabel , Bobbert Thomas , Seifert Joseph , Sindler Amy L. , Pfeiffer Andreas , Hileman Stanley M. , Tschöp Matthias , Banks William A.
Published: April 2006

Adiponectin has recently been reported to generate a negative energy balance by increasing energy expenditure. However, it is unclear whether such effects require the presence and direct action of the adiponectin protein in the central nervous system. In this study, neither radiolabeled nonglycosylated nor glycosylated globular adiponectin crossed the blood-brain barrier (BBB) in mice. In addition, adiponectin was not detectable in human cerebrospinal fluid using various established methods. Using murine cerebral microvessels, we demonstrated expression of adiponectin receptors, which are upregulated during fasting, in brain endothelium. Interestingly, treatment with adiponectin reduced secretion of the centrally active interleukin-6 from brain endothelial cells, a phenomenon that was paralleled by a similar trend of other proinflammatory cytokines. In summary, our data suggest that direct effects of endogenous adiponectin on central nervous system pathways are unlikely to exist. However, the identification of adiponectin receptors on brain endothelial cells and the finding of a modified secretion pattern of centrally active substances from BBB cells provides an alternate explanation as to how adiponectin may evoke effects on energy metabolism.
Novel Leptin Receptor Mutation in NOD/LtJ Mice Suppresses Type 1 Diabetes Progression
Authors: Lee Chul-Ho , Chen Yi-Guang , Chen Jing , Reifsnyder Peter C. , Serreze David V. , Clare-Salzler Michael , Rodriguez Michelle , Wasserfall Clive , Atkinson Mark A. , Leiter Edward H.
Published: April 2006

Recently, we identified in normally type 1 diabetes–prone NOD/LtJ mice a spontaneous new leptin receptor (LEPR) mutation (designated Leprdb-5J) producing juvenile obesity, hyperglycemia, hyperinsulinemia, and hyperleptinemia. This early type 2 diabetes syndrome suppressed intra-islet insulitis and permitted spontaneous diabetes remission. No significant differences in plasma corticosterone, splenic CD4+ or CD8+ T-cell percentages, or functions of CD3+ T-cells in vitro distinguished NOD wild-type from mutant mice. Yet splenocytes from hyperglycemic mutant donors failed to transfer type 1 diabetes into NOD.Rag1−/− recipients over a 13-week period, whereas wild-type donor cells did so. This correlated with significantly reduced (P < 0.01) frequencies of insulin and islet-specific glucose-6-phosphatase catalytic subunit–related protein–reactive CD8+ T-effector clonotypes in mutant mice. Intra-islet insulitis was also significantly suppressed in lethally irradiated NOD-Leprdb-5J/Lt recipients reconstituted with wild-type bone marrow (P < 0.001). In contrast, type 1 diabetes eventually developed when mutant marrow was transplanted into irradiated wild-type recipients. Mitogen-induced T-cell blastogenesis was significantly suppressed when splenic T-cells from both NOD/Lt and NOD-Leprdb-5J/Lt donors were incubated with irradiated mutant peritoneal exudate cells (P < 0.005). In conclusion, metabolic disturbances elicited by a type 2 diabetes syndrome (insulin and/or leptin resistance, but not hypercorticism) appear to suppress type 1 diabetes development in NOD-Leprdb-5J/Lt by inhibiting activation of T-effector cells.
The Effects of Aerobic Exercise on Glucose and Counterregulatory Hormone Concentrations in Children With Type 1 Diabetes
Authors:   The Diabetes Research in Children Network (DirecNet) Study Group
Published: April 2006

OBJECTIVE—To examine the acute glucose-lowering effects of aerobic exercise in children and adolescents with type 1 diabetes.

RESEARCH DESIGN AND METHODS—Fifty children and adolescents with type 1 diabetes (ages 10 to <18 years) were studied during exercise. The 75-min exercise session consisted of four 15-min periods of walking on a treadmill to a target heart rate of 140 bpm and three 5-min rest periods. Blood glucose and plasma glucagon, cortisol, growth hormone, and norepinephrine concentrations were measured before, during, and after exercise.

RESULTS—In most subjects (83%), plasma glucose concentration dropped at least 25% from baseline, and 15 (30%) subjects became hypoglycemic (≤60 mg/dl) or were treated for low glucose either during or immediately following the exercise session. The incidence of hypoglycemia and/or treatment for low glucose varied significantly by baseline glucose, occurring in 86 vs. 13 vs. 6% of subjects with baseline values <120, 120–180, and >180 mg/dl, respectively (P < 0.001). Exercise-induced increases in growth hormone and norepinephrine concentrations were marginally higher in subjects whose glucose dropped ≤70 mg/dl. Treatment of hypoglycemia with 15 g of oral glucose resulted in only about a 20-mg/dl rise in glucose concentrations.

CONCLUSIONS—In youth with type 1 diabetes, prolonged moderate aerobic exercise results in a consistent reduction in plasma glucose and the frequent occurrence of hypoglycemia when preexercise glucose concentrations are <120 mg/dl. Moreover, treatment with 15 g of oral glucose is often insufficient to reliably treat hypoglycemia during exercise in these youngsters.
Metabolic Syndrome
Authors: Eberly Lynn E. , Prineas Ronald , Cohen Jerome D. , Vazquez Gabriela , Zhi Xin , Neaton James D. , Kuller Lewis H. ,   for the Multiple Risk Factor Intervention Trial Research Group
Published: April 2006

OBJECTIVE—To examine the long-term association of metabolic syndrome with mortality among those at high risk for cardiovascular disease (CVD).

RESEARCH DESIGN AND METHODS—A total of 10,950 Multiple Risk Factor Intervention Trial (MRFIT) survivors were followed for mortality an additional median 18.4 years (1980–1999). Proportional hazards models examined multivariate-adjusted risks associated with Adult Treatment Panel III–defined metabolic syndrome conditions, with BMI substituted for waist circumference.

RESULTS—At MRFIT annual visit 6, 4,588 (41.9%) men, mean age (±SD) 53.0 ± 5.9 years, had metabolic syndrome and 6,362 did not. Comparing men with metabolic syndrome to men without, adjusted hazard ratios (HRs) were 1.21 (95% CI 1.13–1.29), 1.49 (1.35–1.64), and 1.51 (1.34–1.70) for 18-year total, CVD, and coronary heart disease mortality, respectively. Among men with metabolic syndrome, elevated glucose (1.54 [1.34–1.78]) and low HDL cholesterol (1.45 [1.17–1.54]) were most predictive of CVD mortality, followed by elevated BMI (1.34 [1.17–1.54]), elevated blood pressure (1.25 [0.98–1.58]), and elevated triglycerides (1.06 [0.86–1.30]). In contrast, for men without metabolic syndrome, the HR for low HDL cholesterol was 1.02 (0.86–1.22). Among metabolic syndrome men with no nonfatal CVD event, smokers with elevated LDL cholesterol showed higher CVD mortality (1.79 [1.22–2.63]) compared with nonsmokers without elevated LDL cholesterol; this additional risk was even greater for metabolic syndrome men with a nonfatal CVD event (2.11 [1.32–3.38]).

CONCLUSIONS—Metabolic syndrome is associated with an increased risk of mortality. Among those with metabolic syndrome, risk is further increased by having more metabolic syndrome conditions, by cigarette smoking, and by elevated LDL cholesterol. Primary prevention of each metabolic syndrome condition should be emphasized, and presence of each condition should be treated in accordance with current guidelines.
Toll-like receptor 2 signaling modulates the functions of CD4+CD25+regulatory T cells
Authors: Liu Haiying , Komai-Koma Mousa , Xu Damo , Liew Foo Y.
Published: April 2006

Toll-like receptors (TLRs) are primary sensors of both innate and adaptive immune systems and play a pivotal role in response against structurally conserved components of pathogens. Synthetic bacterial lipoprotein (BLP) Pam3Cys-SK4 is a TLR2 agonist that is capable of modulating T cell immune responses. We show here that BLP, together with anti-CD3 antibody [T cell receptor (TcR) activation], induced proliferation of both CD4+CD25+regulatory T cells (Tregs) and CD4+CD25−(effector) T cells in the absence of antigen-presenting cells. The expanded Tregs showed a transient loss of suppressive activity. Moreover, BLP rendered effectors resistant to the suppression of Tregs by increasing IL-2 secretion. BLP also transiently suppressed the induction of Foxp3 (X-linked forkhead/winged helix transcription factor) mRNA in Tregs at the first 8–15 h after T cell receptor activation. Consistent with this observation, BLP-stimulated Tregs regained their inhibitory activity and prevented spontaneous colitis induced by effectors in severe combined immunodeficient mice. Our results demonstrate a previously unrecognized pathway by which TLR expressed on T cells may directly modulate the immune response. Thus, during an acute bacterial infection, BLP may rapidly increase the host's adaptive immunity by expanding effectors and also by attenuating the suppressive activity of Tregs. In the process, BLP also expands the Tregs, which recover their suppressive activity when the infection has subsided, in time to limit potential autoimmunity that might result from the overactivated effectors.
Long-range multilocus haplotype phasing of the MHC
Authors: Guo Zhen , Hood Leroy , Malkki Mari , Petersdorf Effie W.
Published: April 2006

Haplotypes are a powerful tool for identifying the genetic basis of common complex diseases. Disease-association mapping requires molecular methods for haplotyping biallelic SNP variation and highly complex polymorphisms. We developed a method for phasing HLA-A, HLA-B, and HLA-DRB1 alleles on chromosome 6 in unrelated individuals. This method uses the highly polymorphic HLA-B locus to discriminate the two HLA haplotypes in heterozygous individuals and its ideal location 1.4 Mbp telomeric to HLA-DRB1 and 1.2 Mbp centromeric to HLA-A to capture 2-Mbp-long genomic DNA. Genomic DNA representing a single HLA-B-captured haplotype is genotyped for HLA-A and HLA-DRB1 alleles and linkage to HLA-B is established. Proof of principle was established in a large blinded study of phase-known samples. Availability of an efficient method for MHC haplotype phase determination will facilitate the mapping of causative MHC-resident genes in many human diseases and has the potential to be broadened to other polymorphic gene complexes.
Case Report: Prenatal Ultrasound Diagnosis of Fetal Diastematomyelia
Authors: Kumar M. , Sarmah T. , Kumar B.
Published: April 2006

Diastematomyelia is a rare congenital malformation in which the spinal cord is divided completely or incompletely by osseous or fibrocartilagenous septum. The division is often asymmetrical and is thought to occur due to splitting of the notochord secondary to adhesions between ectoand entoderm. Most cases are often associated with the abnormalities of the vertebral bodies, including fusion defects, hemi-vertebrae, hypoplasia, kyphoscoliosis, spina-bifida and meningomyelocele. In this report, we describe a case of isolated diastematomyelia of mid-lumbar region detected at 17 weeks of gestation by ultrasound scan. The most striking feature being, detection of the wide lumbar spine from L2 to L4 with intact skin. MRI revealed the split cord with intervening bony spur. Ultrasound scan was performed after birth of the infant to evaluate the defect that confirmed diastematomyelia. Surgical repair of the defect was performed at around 6 months of age. A total of 16 cases of prenatally diagnosed diastematomyelia have been reported in the literature, all with a specific sonographic appearance.
A National Survey of Sonographers and their Reporting Practices in the General Medical Ultrasound Field
Authors: Stoyles Tina , Harrison Gill
Published: April 2006

The purpose of this study was to establish current role extension with specific reference to reporting in departments where sonographers perform general medical ultrasound. It investigates the scope of practice and initiatives that have been negotiated for recognition and remuneration of reporting sonographers, to identify regional variations. A national survey by questionnaire was sent to 503 randomly selected sonographer members of the British Medical Ultrasound Society. Questionnaires were returned from 60% of respondents. Data collected has shown that independent reporting practice by sonographers is becoming increasingly more widespread nationally without significantly greater prevalence in any one region. Roles appear to have developed on an ad hoc basis and vary with different subcategories of reporting practice. Individual Trusts have negotiated different ways of remunerating and recognizing the reporting role, causing disparity. Sonographers independently issue reports across a wide range of ultrasound examinations in a number of departments nationwide and remuneration packages vary throughout the UK. The study recommends further research to establish if sonographer reporting is both an effective and efficient development.
The Fall of Saddam Hussein: Security Council Mandates and Preemptive Self-Defense
Authors: Wedgwood Ruth
Published: April 2006

At long last, the people of Iraq are freed from the brutality of Saddam Hussein. The swift success of the coalition’s military campaign has been followed by predictable difficulties in organizing a hew government, restoring an economy, rebuilding civic society, and quelling violence from remnants of the old regime. But these challenges are kept in scale by recalling a dictator who murdered three hundred thousand fellow citizens. Saddam chose weapons of mass destruction as the central symbol of his domestic and international swagger—using the same internal security apparatus to parry United Nations inspectors and to extinguish domestic political dissent. Removing Iraq’s Ba’athist regime has ended a looming danger to regional neighbors, including Kuwait and Saudi Arabia. The crucial hopes for Middle East peace may also be enhanced by the change. And a new government in Baghdad lessens the chance that weapons matériel will be transferred to ill-intentioned nonstate actors.
International Materials and Domestic Rights: Reflections on Atkins and Lawrence
Authors: Ramsey Michael D.
Published: April 2006

In two recent cases—Atkins v. Virginia and Lawrence v. Texas—amicus briefs urged the U.S. Supreme Court to use international materials to expand the scope of domestic constitutional rights. In a footnote in Atkins and three paragraphs in Lawrence, the Court may have signaled a willingness to listen. Some applaud the beginning of a positive trend. Others—notably Justice Antonin Scalia in dissent in the two cases—condemn the entire project as illegitimate.

Rather than seeking an immediate answer to the question whether international materials should be determinative of domestic rights, this essay makes an indirect approach by asking: if we are to undertake a serious project of using international materials in this way, what would that project look like? Identifying the nature of the project may suggest whether it is the sort of thing we want to undertake, and what the scope of its impact is likely to be.
Muraglitazar, a Novel Dual (α/γ) Peroxisome Proliferator–Activated Receptor Activator, Improves Diabetes and Other Metabolic Abnormalities and Preserves β-Cell Function in db/db Mice
Authors: Harrity Thomas , Farrelly Dennis , Tieman Aaron , Chu Cuixia , Kunselman Lori , Gu Liqun , Ponticiello Randolph , Cap Michael , Qu Fucheng , Shao Chunning , Wang Wei , Zhang Hao , Fenderson William , Chen Sean , Devasthale Pratik , Jeon Yoon , Seethala Ramakrishna , Yang Wen-Pin , Ren Jimmy , Zhou Min , Ryono Denis , Biller Scott , Mookhtiar Kasim A. , Wetterau John , Gregg Richard , Cheng Peter T. , Hariharan Narayanan
Published: April 2006

Muraglitazar, a novel dual (α/γ) peroxisome proliferator–activated receptor (PPAR) activator, was investigated for its antidiabetic properties and its effects on metabolic abnormalities in genetically obese diabetic db/db mice. In db/db mice and normal mice, muraglitazar treatment modulates the expression of PPAR target genes in white adipose tissue and liver. In young hyperglycemic db/db mice, muraglitazar treatment (0.03–50 mg · kg−1 · day−1 for 2 weeks) results in dose-dependent reductions of glucose, insulin, triglycerides, free fatty acids, and cholesterol. In older hyperglycemic db/db mice, longer-term muraglitazar treatment (30 mg · kg−1 · day−1 for 4 weeks) prevents time-dependent deterioration of glycemic control and development of insulin deficiency. In severely hyperglycemic db/db mice, muraglitazar treatment (10 mg · kg−1 · day−1 for 2 weeks) improves oral glucose tolerance and reduces plasma glucose and insulin levels. In addition, treatment increases insulin content in the pancreas. Finally, muraglitazar treatment increases abnormally low plasma adiponectin levels, increases high–molecular weight adiponectin complex levels, reduces elevated plasma corticosterone levels, and lowers elevated liver lipid content in db/db mice. The overall conclusions are that in db/db mice, the novel dual (α/γ) PPAR activator muraglitazar 1) exerts potent and efficacious antidiabetic effects, 2) preserves pancreatic insulin content, and 3) improves metabolic abnormalities such as hyperlipidemia, fatty liver, low adiponectin levels, and elevated corticosterone levels.
A vHNF1/TCF2-HNF6 Cascade Regulates the Transcription Factor Network That Controls Generation of Pancreatic Precursor Cells
Authors: Poll Aurélie V. , Pierreux Christophe E. , Lokmane Ludmilla , Haumaitre Cécile , Achouri Younes , Jacquemin Patrick , Rousseau Guy G. , Cereghini Silvia , Lemaigre Frédéric P.
Published: April 2006

Generation of pancreatic precursor cells in the endoderm is controlled by a network of transcription factors. Hepatocyte nuclear factor-6 (HNF6) is a key player in this network, because it controls the initiation of the expression of pancreatic and duodenal homeobox 1 (Pdx1), the earliest marker of pancreatic precursor cells. To further characterize this network, we have investigated how the expression of HNF6 is controlled in mouse endoderm, by using in vitro and in vivo protein-DNA interaction techniques combined with endoderm electroporation, transgenesis, and gene inactivation in embryos. We delineated Hnf6 regulatory regions that confer expression of a reporter gene in the embryonic endoderm but not in extraembryonic visceral endoderm. HNF6 expression in the embryonic endoderm was found to depend on an intronic enhancer. This enhancer contains functional binding sites for the tissue-specific factors of the forkhead box A and HNF1 families. Among the latter, variant HNF1 (vHNF1)/TCF2, which is expressed before HNF6 in the endoderm, was found to be critical for HNF6 expression. Therefore, the sequential activation of vHNF1, HNF6, and Pdx1 in the endoderm appears to control the generation of pancreatic precursors. This cascade may be used to benchmark in vitro differentiation of pancreatic precursor cells from embryonic stem cells, for cell therapy of diabetes.
Natural Antibiotics and Insulin Sensitivity
Authors: Gubern Carme , López-Bermejo Abel , Biarnés Josefina , Vendrell Joan , Ricart Wifredo , Fernández-Real José Manuel
Published: April 2006

The innate immune system can immediately respond to microorganism intrusion by helping to prevent further invasion. Bactericidal/permeability-increasing protein (BPI) is a major constituent of neutrophils that possesses anti-inflammatory properties. Inflammation is increasingly recognized as a component of the metabolic syndrome. We hypothesized that the production of BPI could be linked to insulin sensitivity and glucose tolerance. We studied circulating BPI across categories of glucose tolerance. We also studied whether these cross-sectional associations were of functional importance. For this reason, we investigated circulating bioactive lipopolysaccharide and the effects of changing insulin action—after treatment with an insulin sensitizer (metformin)—on circulating BPI in subjects with glucose intolerance. Finally, we tested whether a 3′-untranslated region (UTR) BPI polymorphism led to differences in BPI and insulin action among nondiabetic subjects. Age- and BMI-adjusted circulating BPI was significantly lower among patients with type 2 diabetes. Circulating BPI correlated negatively with fasting and postload glucose and insulin concentrations. In subjects with glucose intolerance, BPI was also linked to BMI, waist-to-hip ratio, and age- and BMI-adjusted insulin sensitivity. Bioactive lipopolysaccharide was negatively correlated with circulating BPI (r = −0.57, P < 0.0001) and positively with plasma lipopolysaccharide-binding protein (r = 0.54, P = 0.002). In parallel to improved insulin sensitivity, plasma BPI significantly increased in the metformin group but not in the placebo group. A 3′-UTR BPI polymorphism was simultaneously associated with plasma BPI concentration, waist-to-hip ratio, fasting and postload insulin concentration, fasting plasma triglycerides, and insulin sensitivity. These findings suggest that this component of the innate immune system is associated with metabolic pathways.
Treatment Disparities in the Care of Patients With and Without Diabetes Presenting With Non–ST-Segment Elevation Acute Coronary Syndromes
Authors: Brogan Gerard X. , Peterson Eric D. , Mulgund Jyotsna , Bhatt Deepak L. , Ohman E. Magnus , Gibler W. Brian , Pollack Charles V. , Farkouh Michael E. , Roe Matthew T.
Published: April 2006

OBJECTIVE—The objective of this study was to characterize treatment patterns among patients with diabetes presenting with non–ST-segment elevation (NSTE) acute coronary syndromes (ACSs).

RESEARCH DESIGN AND METHODS—We compared adherence to treatment recommendations from the American College of Cardiology (ACC)/American Heart Association (AHA) guidelines for NSTE ACS among 46,410 patients from 413 U.S. hospitals that were included in the Can Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes with Early Implementation of the ACC/AHA Guidelines (CRUSADE) quality improvement initiative. Patients were stratified as nondiabetic, non–insulin-dependent diabetic (type 2 diabetic), and insulin-treated diabetic.

RESULTS—Insulin-treated diabetic patients were less likely than nondiabetic patients to receive aspirin (adjusted odds ratio 0.83 [95% CI 0.74–0.93]), β-blockers (0.89 [0.83–0.96]), heparin (0.90 [0.83–0.98]), and glycoprotein IIb/IIIa inhibitors (0.86 [0.79–0.93]). Type 2 diabetic patients were treated similarly to nondiabetic patients. After adjustment for differences in clinical characteristics, insulin-treated diabetic patients were significantly less likely than nondiabetic patients to receive cardiac catheterization within 48 h of presentation (0.80 [0.74–0.86]) or percutaneous coronary intervention (0.87 [0.82–0.94]). Compared with nondiabetic patients, insulin-treated diabetic and type 2 diabetic patients were more likely to undergo coronary artery bypass grafting (1.34 [1.21–1.49] and 1.35 [1.26–1.44]). In-hospital mortality rates were higher in insulin-treated diabetic (6.8%) and type 2 diabetic (5.4%) than in nondiabetic (4.4%) patients.

CONCLUSIONS—Diabetic patients have a higher risk of mortality than nondiabetic patients, yet physicians adhere to the ACC/AHA NSTE ACS guidelines less often when treating diabetic patients, particularly insulin-treated diabetic patients. Increased use of guideline-recommended therapies and early invasive management strategies in diabetic patients may improve their outcomes.
Unusually quick development of a 4000 nT substorm during the initial 10 min of the 29 October 2003 magnetic storm
Authors: Yamauchi M. , Iyemori T. , Frey H. , Henderson M.
Published: April 2006

Global geomagnetic field data, IMAGE FUV data, and many other in situ observations are presented for the initial 10 min of the magnetic storm starting 29 October 2003 at around 0610 UT. Within 1 min after sudden commencement (SC), two independent strong westward ionospheric electrojets (>2000 nT) at the inner magnetospheric region started simultaneously, one in the evening‐midnight sector and the other in the morning sector. Both activities expanded and accompanied auroral expansion. The locations (inner magnetosphere), morphologies (expansion), and intensities (>2000 nT) of both activities fall into substorm expansive phases. Having such simultaneous independent 2000 nT level expansions makes this event unique. The interplanetary magnetic field condition before the SC was not favorable in causing an AL < −2000 nT activity. A timing analysis indicates that these strong westward electrojets were most likely triggered by the interplanetary shock, with the triggering location not farther than the geosynchronous distance. They are also probably maintained by the direct energy pumping from the solar wind because cross‐tail current derived from the closely located GOES‐10 and Polar did not decrease very much during this period. A local but even stronger geomagnetic (nearly 4000 nT) and auroral activity started only 6 min after the start of SC at postmidnight where and when the above two expanding activities met each other, although the relation between the onset of 4000 nT activity and the preceding expansions is not clear. The suddenness of this third activity (3000 nT change within 2 min) is another unique feature.
An upper bound on the solar radar cross section at 50 MHz
Authors: Coles W. A. , Harmon J. K. , Sulzer M. P. , Chau J. L. , Woodman R. F.
Published: April 2006

We have made 16 unsuccessful attempts, in February and October 2003, and February 2004, to observe solar echoes using the 50 MHz radar at Jicamarca in Peru. The upper bound that we have determined on the solar cross section is significantly lower than the average of earlier reported observations. In this paper we will describe the observations, discuss the noise and interference from solar bursts, and suggest possible reasons why the echo might be weaker than expected.
Expression profiling the developing mammalian enteric nervous system identifies marker and candidate Hirschsprung disease genes
Authors: Heanue Tiffany A. , Pachnis Vassilis
Published: April 2006

The enteric nervous system (ENS) is composed of neurons and glial cells, organized as interconnected ganglia within the gut wall, which controls persistalsis of the gut wall and secretions from its glands. The
Ret
receptor tyrosine kinase is expressed throughout enteric neurogenesis and is required for normal ENS development; humans with mutations in the
RET
locus have Hirschsprung disease (HSCR, an absence of ganglia in the colon), and mice lacking
Ret
have total intestinal aganglionosis. The
Ret
mutant mouse provides a tool for identifying genes implicated in development of the ENS. By using RNA from WT and
Ret
mutant (aganglionic) gut tissue and DNA microarrays, we have conducted a differential screen for ENS-expressed genes and have identified hundreds of candidate ENS-expressed genes. Forty-seven genes were selected for further analysis, representing diverse functional classes. We show that all of the analyzed genes are expressed in the ENS and that the screen was sensitive enough to identify genes marking only subpopulations of ENS cells. Our screen, therefore, was reliable and sensitive and has identified many previously undescribed genes for studying ENS development. Moreover, two of the genes identified in our screen
Arhgef3
and
Ctnnal1
, have human homologues that map to previously identified HSCR susceptibility loci, thus representing excellent candidates for HSCR genes. This comprehensive profile of ENS gene expression refines our understanding of ENS development and serves as a resource for future developmental, biochemical, and human genetic studies.