bluuebunny/crossref_metadata_2025 huggingface dataset:
Crystal structures and magnetic properties of Fe–N thin films deposited by dc magnetron sputtering
Authors: Zheng Wei Tao , Wang Xin , Kong Xianggui , Tian Hongwei , Yu Shansheng , Zhao Zhudi , Li Xiaotian
Published: December 2004

Fe–N thin films were deposited on glass substrates by dc magnetron sputtering under various Ar∕N2 discharge conditions. Crystal structures and elemental compositions of the films were characterized by X-ray diffraction and X-ray photoelectron spectroscopy. Magnetic properties of the films were measured using a superconducting quantum interference device magnetometer. Films deposited at different N2∕(Ar+N2) flow ratios were found to have different crystal structures and different nitrogen contents. When the flow ratios were 60%, 50%, and 30%, a nonmagnetic single-phase FeN was formed in the films. At the flow ratio of 10%, two crystal phases of γ′-Fe4N and ε-Fe3N were detected. When the flow ratio reduced to 5%, a mixture of α-Fe, ε-Fe3N, FeN0.056, and α″-Fe16N2 phases was obtained. The value of saturation magnetization for the mixture was found to be larger than that of pure Fe.
Subsolidus phase relations and crystal structures in the Pr1+xBa2−xCu3O7±δ system at 950 °C
Authors: Song G. B. , Liang J. K. , Liu F. S. , Yang L. T. , Luo J. , Rao G. H.
Published: December 2004

Pr1+xBa2−xCu3O7±δ solid solution was investigated by means of X-ray powder diffraction and Rietveld analysis. Single-phase PrBa2Cu3O7±δ (Pr123) can be synthesized under a Pr-rich condition by sintering at 950 °C in air. The solubility of Pr1+xBa2−xCu3O7±δ solid solution is 0.08≤x≤0.80. The structure of Pr1+xBa2−xCu3O7±δ is orthorhombic for 0.08≤x<0.30, and transforms into tetragonal for 0.30≤x≤0.80. To form single-phase Pr123, the Ba sites in the Pr123 structure are partially occupied by excess Pr ions, and the smallest amount of excess Pr is x=0.08. Meanwhile, all Ba ions stay in the Ba sites.
An X-ray scattering study on inverted Ge–Si huts grown at low temperatures
Authors: Xu J. , Wu X. S. , Qian B. , Feng J. F. , Jiang S. S. , Tan W. S. , Chen C. J. , Chen X. , Sun M. H. , Wu Z. H.
Published: December 2004

Ge–Si inverted huts, which formed at the Si∕Ge interface of Si∕Ge superlattice grown at low temperatures, have been measured by X-ray diffraction, grazing incidence X-ray specular and off-specular reflectivities, and transmission electron microscopy (TEM). The surface of the Si∕Ge superlattice is smooth, and there are no Ge–Si huts appearing on the surface. The roughness of the surfaces is less than 3 Å. Large lattice strain induced by lattice mismatch between Si and Ge is found to be relaxed because of the intermixing of Ge and Si at the Si∕Ge interface.
Regulation of tissue factor-induced coagulation and platelet aggregation in flowing whole blood
Authors: Kuijpers Marijke , Nieuwenhuys Cécile , Feijge Marion , Kloots Willem , Giesen Peter , Jerling Johann , oude Egbrink Mirjam , Heemskerk Johan
Published: December 2004

Photochemically induced thrombosis (a thrombin-dependent process) was measured in rats treated with moderate doses of anticoagulants, but which appeared to be unchanged. We considered the possibility that platelet-inhibiting agents, which also indirectly inhibit coagulation, would act as more potent antithrombotic agents.Inhibitors used as such were prostaglandin E1 (PGE1), which elevates cyclic AMP levels, and the P2Y12 ADP-receptor antagonist,AR-C69931MX. Effects of these agents were investigated in an ex vivo model system, in which whole blood under coagulant conditions was perfused over fibrinogen at defined wall shear rate. Perfusion of blood (rat or human) in the presence of tissue factor resulted in deposition of activated platelets and subsequent aggregate formation, along with exposure of procoagulant phosphatidylserine (PS) on the platelet surface and formation of fibrin fibers. In the presence of PGE1 aggregation was completely inhibited,but platelet adhesion and PS exposure were only party reduced, while fibrin formation was hardly affected. Treatment with AR-C69931MX caused similar, but less complete effects.These results indicate that in tissue factor- triggered blood under conditions of flow:(i) the platelet procoagulant response is independent of aggregate formation; (ii) the platelet-inhibiting effect of PGE1 and AR-C69931MX is sufficient to suppress aggregation, but not platelet adhesion and coagulation. These platelet inhibitors thus maintain their aggregation- inhibiting effect at sites of thrombin formation.
Defective collagen-induced platelet activation in two patients with malignant haemopathies is related to a defect in the GPVI-coupled signalling pathway
Authors: Huisse Marie , Boval Bernadette , Hainaud Patricia , Robert Annie , Fauvel-Lafève Françoise , Jandrot-Perrus Martine , Bellucci Sylvia
Published: December 2004

The occurrence of a thrombocytopathy concomitantly to the development of a malignant haemopathy has been reported for some time, but little is known about the mechanism(s) involved in the platelet dysfunction. Platelet glycoprotein VI (GPVI) has now been identified as a principal platelet receptor for collagen. In this paper, we report the cases of two patients with a myelodysplasia and a B lymphopathy, respectively, who presented with thrombocytopathy in relation to a defective GPVI-mediated platelet reactivity to collagen. Thus, with regard to the different steps of adhesion, activation secretion or aggregation, patients’ platelet responses to collagen and to the GPVI specific agonists, collagen related peptide (CRP) or convulxin were null or dramatically impaired. Platelet responses to other agonists ADP, TRAP,Arachidonic acid were normal or showed only a moderate decrease. GPVI content was repeatedly normal, and binding of specific ligands, such as convulxin, satisfactory. Nevertheless, specific activating monoclonal antibodies and convulxin failed to induce platelet secretion; collagen, CRP or convulxin were unable to provoke calcium mobilisation. Furthermore, using a perfusion chamber model, we showed that ex vivo collagen-induced thrombi formation was very impaired.Taken together,these data provide evidence, for the first time, of an acquired defect in GPVI-mediated platelet reactivity to collagen, which reflects data observed in constitutional GPVI deficiencies, in two patients with malignant haemopathies.
Long lives, short indications
Authors: Ku Grace , Billett Henny
Published: December 2004

Vena cava filters have been in use for decades to prevent pulmonary embolization from deep venous thrombosis. These filters have been shown to be effective, with fairly low rates of filter migration, fracture and thrombosis. However considering that filters remain in situ for the life of the patient and that studies do not show increased longevity in patients with filters, any complications from filters are significant concerns. In addition, often patients require filters for only temporary indications, e.g. contraindication for anticoagulation because of impending procedures, or for only a transient risk period, as in trauma or pregnant patients. In these cases, removable filters may be more appealing. This review will examine the different types of removable filters and the indications in which removable filters may have an advantage over permanent filters.
Two parallel prothrombin activator systems in Australian rough-scaled snake, Tropidechis carinatus
Authors: Reza Md. Abu , Swarup Sanjay , Kini Manjunatha
Published: December 2004

It is uncommon for similar pathways/systems to be involved in highly divergent functions within single organisms. Earlier, we have shown that trocarin D, a venom prothrombin activator, from the Australian rough-scaled snake Tropidechis carinatus, is structurally and functionally similar to the blood coagulation factor Xa (FXa). The presence of a haemostatic system in these snakes implies that they have two parallel prothrombin activating systems: one in the plasma, that participates in the life saving process of blood clotting and the other in their venom, where it acts as a toxin. Here, we report the complete cDNA sequence encoding the blood coagulation factor X (FX) from the liver of T. carinatus. Deduced T. carinatus FX sequence shows ~80% identity with trocarin D but ~50% identity with the mammalian FX. Our present study confirms the presence of two separate genes – one each for FX and trocarin D, that code for similar proteins in T. carinatus snake. These two genes have different expression sites and divergent uses suggesting that snake venom prothrombin activators have probably evolved by the duplication of the liver FX gene and subsequently marked for tissue-specific expression in the venom gland.
Prevention of cardiovascular disease in type-2 diabetes: How to improve the clinical efficacy of aspirin
Authors: Totani Licia , Rotondo Serenella , Lorenzet Roberto , Tognoni Gianni , De Berardis Giorgia , Nicolucci Antonio , Evangelista Virgilio
Published: December 2004

Atherosclerotic cardiovascular disease and its thrombotic complications are the principal causes of morbidity and mortality in patients with type-2 diabetes.Aspirin reduces the risk of thrombotic events in a broad range of patients with vascular disease and, in selected individuals, is beneficial for primary prevention. Although recommended by existing guidelines,in secondary and in primary prevention trials the clinical efficacy of low-dose aspirin in patients with diabetes appears to be substantially lower than in individuals without diabetes. In this review, we discuss possible mechanisms that may contribute to reduce the antithrombotic activity of aspirin in diabetes.We also discuss adjuvant therapies used in diabetic patients that may potentially improve the antithrombotic efficacy of aspirin.
Pharmacodynamic resistance to warfarin associated with a Val66Met substitution in vitamin K epoxide reductase complex subunit 1
Authors: Harrington Dominic , Underwood Sarah , Morse Colin , Shearer Martin , Tuddenham Edward , Mumford Andrew
Published: December 2004

The gene encoding vitamin K epoxide reductase complex subunit 1 (VKORC1), a component of the enzyme that is the therapeutic target site for warfarin, has recently been identified. In order to investigate the relationship betweenVKORC1 and warfarin dose response, we studied theVKORC1 gene (VKORC1) in patients with warfarin resistance. From a study group of 820 patients, we identified 4 individuals who required more than 25 mg of warfarin daily for therapeutic anticoagulation.Three of these had serum warfarin concentrations within the therapeutic range of 0.7–2.3 mg/l and showed wild-type VKORC1 sequence. The fourth warfarin resistant individual had consistently high ( ≥ 5.7 mg/l) serum warfarin concentrations, yet had no clinically discernible cause for warfarin resistance. VKORC1 showed a heterozygous 196G→ A transition that predicted aVal66Met substitution in the VKORC1 polypeptide. This transition was also identified in 2 asymptomatic family members who had never received warfarin.These individuals had normal vitamin-K dependent coagulation factor activities and undetectable serum PIVKAII and vitamin K 1 2,3 epoxide suggesting that their basal vitamin K epoxide reductase activity was not adversely affected by the VKORC1 Val66Met substitution.The association between a nucleotide transition in VKORC1 and pharmacodynamic warfarin resistance supports the hypothesis that VKORC1 is the site of action of warfarin and indicates that VKORC1 sequence is an important determinant of the warfarin dose response.
Empowering the end-user: Business Information Resources Survey, 2003
Authors: Foster Allan , Foster Pam
Published: December 2004

Surveys the use of business information in UK libraries, based on a questionnaire mailed in November 2002 to libraries/information departments.
Regional data Catching up... fast! Improvements in Central and East European business information
Authors: Konn Tanya
Published: December 2004

The introduction of more liberal markets and the broadening consequences of globalization have had transforming repercussions upon the collection and dissemination of Central and East European (CEE) business information. Thirteen years after the original political upheavals and the freeing of the individual countries’ markets, the volume of information produced in English and indigenous languages has increased enormously, forms of dissemination match those in developed economies, and qualitative standards have improved significantly. Given continuing, and generally expected, economic improvements these trends are likely to continue. In areas where compilation and description comprise the main information source contents (directories, company listings, factual news and relevant legislation) many services and products have already reached international standards. However, the same is not the case for company information beyond the contact and locating levels. This is due to the existing state of company law and the employment of opaque accountancy practices in a number of CEE countries, where it can be very difficult to obtain trustworthy assessments of the financial standing of individual companies. These issues are currently being addressed by those countries readying themselves for membership of the European Union and preparing them to embrace conformity to common standards.
Paying for it: the current state of the information broking market
Authors: Broadhurst Dominic
Published: December 2004

This article attempts to set the scene for the current state of the information broking industry and provide some prognosis for its future. There is no doubt that the nature of information broking has undergone considerable change in recent years. Much of the market for traditional intermediary services has vanished and the author provides an analysis of the supply of company information to highlight these changes. The impact of the Internet on the industry is assessed and two contrasting case studies of players within the sector are also provided in a commentary on the current state of the industry. Thoughts on how the future will look are also offered, with the conclusion reached that, to prosper, information brokers must adapt, innovate and be totally intuitive to the client’s needs.
Radical company law reform: implications for researching companies
Authors: Murphy Christopher
Published: December 2004

Publicly available information about companies arises for two reasons: either a firm releases it voluntarily or it is compelled by law to reveal it to the public. The legal requirements laid upon a company to file documents open to public inspection have a huge impact on what researchers can find out about them. The UK Government is currently reforming company law for the first time in over 150 years and this will include dramatic changes in filing requirements with a major impact on corporate research. It will be essential for researchers on companies to have a detailed understanding of the effect of the Government’s proposals. Although a new Companies Bill will be introduced, the Government recognizes that this method of legislative catching up is an unsatisfactory way of coping with changes in technology and business practice. It therefore proposes to enshrine certain fundamental principles in this primary legislation, while providing ample scope to make technical changes in company law through secondary legislation. Ministers will have the power to effect these by signing Statutory Instruments instead of resorting to the slow and complex process of getting parliamentary bills enacted. Other provisions of the new company law will cover: the removal of filing exemptions for small and medium sized private companies; shorter deadlines for filing accounts; the abolition of Directors’ reports; an Operating and Financial Review (OFR) to be compiled by larger companies; raising of the audit threshold; a Combined Code on Corporate Governance; a single company constitution; changed duties for company officers; and special provision for shareholder information.
Work-Life Balance: How Life Coaching Can Help
Authors: McIntosh Stewart
Published: December 2004

The growing dissatisfaction by the UK Government with the way that work increasingly dominates the lives of employees, particularly managers, at the expense of their family life, led to “Work-Life Balance Week”, part of the Government’s drive to encourage the idea of flexible working arrangements, family-friendly policies and the enhancement of employees’ lives. The Work-Life Balance campaign, launched in March 2000, aims is to convince employers of the economic benefits of work-life balance and of the need for the introduction of flexible working arrangements in the form of: flexitime; staggered hours; time off in lieu; compressed working hours and similar measures. The need for work-life balance has been clearly shown by the results of employee surveys, conducted by bodies such as The Work Foundation (formerly the Industrial Society), which revealed that UK men now strive to be different from their fathers in their approach to home and family (over 60 per cent stating that they are more likely to feel guilty about neglecting domestic duties than their fathers did). The author, who is a life coach specializing in advising people on their work-life balance and career development, sets out the business case for work-life balance and explains how life coaches can play a vital role in helping individuals to restore the balance between their lives and the work of organizations. Sets out the ways in which life coaching can help people to balance their work, home, leisure and personal development. Concludes that the success of life coaching rests on the ability to lay bare the individual’s underlying values and so reveal the factors causing balance or imbalance.
Delivering a Parliamentary Information Service in a Corporate Environment
Authors: Picton Howard
Published: December 2004

UK companies engaged in financial and related services have long acknowledged the need for some sort of parliamentary affairs information service to underpin their activities and assist them in their work. These companies may develop their own in-house services or may outsource the work to external “public affairs” firms to keep them abreast of such information. Reviews the characteristics of such information services in the context of the work of the Parliamentary Affairs Unit (PAU) at the author’s institution, the Bank of England. Examines the range of available information sources and the ways in which these fit into the work of the Bank, particularly since 1997, when the Bank was granted operational independence from Parliament for setting interest rates. The workings of Parliament are discussed in terms of the activities of the House of Commons, the House of Lords and the Crown, in order to understand the nature of the information generated. Focuses on the Bank of England’s PAU to illustrate its structure and role; the Parliamentary information that is most relevant; Westminster-based information; legislative-based information; tracking legislation through Parliament; biographical information; backbencher information; Whitehall (Government) information; and political party information. Concludes with notes on how alerting services can be constructed around parliamentary information sources and the importance of currency with this type of information.
Building for Business Knowledge: Constructing a New Business School in the Heart of London
Authors: Holtham Clive
Published: December 2004

An account is given of the planning and construction of the new award-winning building to house the Cass Business School, City of London (formerly the Business School of City University), opened in May 2003, from the viewpoint of the way in which considerations of information and knowledge management permeated the fundamental concept of the building as well as its detailed design features. A major aim of the building was that it should serve as: a world class place for staff, students and visitors to create and share knowledge; a comfortable, efficient and sustainable building; a visible symbol of the organization’s goal to be the intellectual hub of the City of London; a building that helps staff to achieve cultural change internally by breaking down barriers between departments and between different types of staff; and a flexible building capable of being adapted to changing models of learning/teaching or changing economic circumstances. Three additional concepts emerged from the design process: that it should be the intellectual hub of the City of London; that it should combine the very best of technology with a great diversity of opportunities for face-to-face interaction; and that there should be full commercial flexibility. Concludes that the design process benefited greatly from innovative work by researchers, architects, universities and other organizations worldwide that are concerned with knowledge work. The outcome was an acceptance that there is no one right way to design a modern university but each organization needs to carry out its own strategic review to decide what it wants the building to achieve, before there can be any consideration of detailed design work.
The Japanese Business Information Scene: Birth of the New Social Library for Free Agents in the Context of Knowledge Management in Japan
Authors: Kobayashi Mami
Published: December 2004

When attempting to obtain and understand Japanese business information, most non Japanese don’t understand how important it is not only to deal with the language issue but also to know the Japanese business culture and philosophy. However, Japan is now in a period of large scale transition from Japanese style business to global business, and this change is affecting the delivery of business information for local people. One example of the change is the newly established membership-based Academyhills Roppongi Library, where people can get the latest business data as free agents, unconstrained by the limits faced by company workers.
RNAi-induced down-regulation of FLT3 expression in AML cell lines increases sensitivity to MLN518
Authors: Walters Denise K. , Stoffregen Eric P. , Heinrich Michael C. , Deininger Michael W. , Druker Brian J.
Published: December 2004

FMS-like tyrosine kinase 3 (FLT3) is a receptor tyrosine kinase that is constitutively activated in approximately 30% of acute myelogenous leukemia (AML) patients and appears to confer an adverse prognosis. Thus, development of inhibitors and/or antibodies that specifically target FLT3 has been of substantial interest. In this regard, phase 1 and 2 trials involving FLT3 inhibitors have recently reported FLT3 inhibition and leukemic blast reduction in some patients. Despite this, issues such as specificity and resistance need to be addressed. Consequently, the development of alternative approaches for targeting FLT3 would be of great consequence. In the present report, we demonstrate that FLT3 siRNA effectively down-regulates FLT3 expression in Ba/F3 cells transfected with FLT3 containing an activating internal tandem duplication (ITD) in the juxtamembrane domain and FLT3-ITD–positive Molm-14 human leukemia cells. Treatment with the FLT3 siRNA results in growth inhibition and apoptosis of these cells. Furthermore, siRNA-induced down-regulation of FLT3 increased the sensitivity of both cell lines to treatment with the FLT3 inhibitor MLN518. This illustrates the potential benefit of combined therapeutic approaches.
Plag1 and Plagl2 are oncogenes that induce acute myeloid leukemia in cooperation with Cbfb-MYH11
Authors: Landrette Sean F. , Kuo Ya-Huei , Hensen Karen , van Waalwijk van Doorn-Khosrovani Sahar Barjesteh , Perrat Paola N. , Van de Ven Wim J. M. , Delwel Ruud , Castilla Lucio H.
Published: December 2004

Recurrent chromosomal rearrangements are associated with the development of acute myeloid leukemia (AML). The frequent inversion of chromosome 16 creates the CBFB-MYH11 fusion gene that encodes the fusion protein CBFβ-SMMHC. This fusion protein inhibits the core-binding factor (CBF), resulting in a block of hematopoietic differentiation, and induces leukemia upon the acquisition of additional mutations. A recent genetic screen identified Plag1 and Plagl2 as CBFβ-SMMHC candidate cooperating proteins. In this study, we demonstrate that Plag1 and Plagl2 independently cooperate with CBFβ-SMMHC in vivo to efficiently trigger leukemia with short latency in the mouse. In addition, Plag1 and Plagl2 increased proliferation by inducing G1 to S transition that resulted in the expansion of hematopoietic progenitors and increased cell renewal in vitro. Finally, PLAG1 and PLAGL2 expression was increased in 20% of human AML samples. Interestingly, PLAGL2 was preferentially increased in samples with chromosome 16 inversion, suggesting that PLAG1 and PLAGL2 may also contribute to human AML. Overall, this study shows that Plag1 and Plagl2 are novel leukemia oncogenes that act by expanding hematopoietic progenitors expressing CbFβ-SMMHC.
Cavity pressure control of powder injection moulding machines
Authors: Yiğit İlhami , Ercan Yücel , Saritaş Süleyman
Published: December 2004

In this study, cavity pressure control of a computer controlled powder injection moulding setup driven by an electro-hydraulic servovalve was investigated both theoretically and experimentally. For this purpose, a detailed system model of a powder injection moulding machine was developed and the important parameters that affect the system behaviour were determined by carrying out computer simulations. In light of the simulation results, a closed-loop control system was designed and manufactured. The control system was implemented to a specially designed powder injection moulding setup. Comparisons of the theoretical and experimental results demonstrate that the developed system model describes the dynamic behaviour of the system satisfactorily. The results of experiments show that accurate control of the cavity pressure can be achieved by the proposed control system.
On the IMC-based synthesis of the feedback block of ISA PID regulators
Authors: Leva Alberto , Colombo Antonio M.
Published: December 2004

This paper presents and analyses a method for synthesizing the feedback block of a 2-d.o.f. real PID regulator, referring to the widely used ISA structure and particularly well suited for auto-tuning. A rigorous stability, performance, robustness and consistency analysis is provided, extending some results of the previous literature. An objective criterion is devised for selecting the method’s (single) design parameter based on the process model employed and an overestimate of the corresponding process/model mismatch. Both simulation and practical application examples are reported.
Carnitine and Sports Medicine: Use or Abuse?
Authors: BRASS ERIC P.
Published: December 2004

Abstract: Carnitine has important roles in skeletal muscle bioenergetics. Skeletal muscle carnitine deficiency is associated with profound impairment of muscle function. It has thus been natural to ask if carnitine supplementation can improve skeletal muscle function and athletic performance in healthy individuals. Oral carnitine doses of several grams cause no significant clinical toxicity, further encouraging the use of carnitine as a supplement. Despite this strong foundation and 20 years of research, no compelling evidence exists that carnitine supplementation can improve physical performance in healthy subjects. The available data have been reviewed in recent publications. Several key issues are relevant to a potential therapeutic benefit of carnitine supplementation, and addressing these may provide insight into trials of carnitine therapy in healthy subjects: (1) Can carnitine supplementation increase skeletal muscle carnitine content in healthy subjects? Muscle carnitine content is not easily increased with carnitine supplementation. This reflects both the systemic pharmacokinetics of carnitine and the systems controlling transmembrane transport of carnitine in skeletal muscle. (2) How much carnitine is required to support optimal metabolism in skeletal muscle? Data are not available to definitively define the relationship between muscle carnitine content and muscle metabolic function. Extrapolation of data from several models suggests that very low amounts of carnitine are required to support muscle function. (3) Does carnitine supplementation alter energy homeostasis in healthy subjects? Several, but not all, studies suggest that subjects on carnitine supplementation have altered regulation of fuel homeostasis. However, the mechanisms of these changes, the tissues affected, and the relevance of these phenomena to exercise performance are all ill defined. (4) How can changes in performance be assessed in healthy subjects? Most studies have failed to demonstrate an objective performance improvement in healthy subjects taking carnitine. However, these negative studies must be interpreted with caution. Performance studies in athletes are conducted against a background of aggressive training regimens and nutritional interventions. Small changes, which may be very important to the athlete, may be very hard to objectify in the laboratory. Assessments must differentiate between changes in maximal aerobic capacity, ability to sustain effort at varied workloads, and the subject's perception of exertion. The interaction of carnitine supplementation with exercise training may be particularly important on theoretical and experimental bases. Systematic research in each of these areas is required to better understand the physiology, biochemistry, and pharmacology of carnitine supplementation. While data do not allow a conclusion to be drawn that carnitine is beneficial, the negative has not been proven either.
Carnitine and Peripheral Arterial Disease
Authors: HIATT WILLIAM R.
Published: December 2004

Abstract: Patients with peripheral arterial disease (PAD) who become symptomatic with claudication (approximately one‐third of the population) have a marked impairment in exercise performance and overall functional capacity. Patients with claudication have a peak oxygen consumption measured during graded treadmill exercise testing that is 50% of that in age‐matched normal subjects, and also report great difficulty in walking relatively short distances, even at a slow walking speed. The reduced walking capacity is associated with impairment in activities of daily living and quality of life. Thus, claudication is highly limiting to the physical functioning of daily activities. Improving mobility and improving the reduced quality of life are therefore major goals of treatment. Patients with PAD develop metabolic abnormalities in the skeletal muscles of the lower extremity. These abnormalities include impairment in ischemic muscle mitochondrial electron transport chain activity and accumulation of intermediates of oxidative metabolism (acylcarnitines). Patients with the greatest accumulation of muscle acylcarnitines have the most impaired exercise performance. Thus, claudication is not simply the result of reduced blood flow, and alterations in skeletal muscle metabolism are part of the pathophysiology of the disease. l‐Carnitine and propionyl‐l‐carnitine may improve the metabolism and exercise performance of ischemic muscles. l‐Carnitine in a dose of 2 grams twice daily improved treadmill performance, but propionyl‐l‐carnitine (an acyl form of carnitine) was more effective than l‐carnitine in improving treadmill walking distance. In two multicenter trials of a total of 730 patients, initial and maximal treadmill walking distance improved more with propionyl‐l‐carnitine than placebo. The drug also improved quality of life and had minimal side effects as compared with placebo. Propionyl‐l‐carnitine has not been approved for use in the United States.
Carnitine in Type 2 Diabetes
Authors: MINGRONE GELTRUDE
Published: December 2004

Abstract:Carnitine, the l‐β‐hydroxy‐γ‐N‐trimethylaminobutyric acid, is synthesized primarily in the liver and kidneys from lysine and methionine. Carnitine covers an important role in lipid metabolism, acting as an obligatory cofactor for β‐oxidation of fatty acids by facilitating the transport of long‐chain fatty acids across the mitochondrial membrane as acylcarnitine esters. Furthermore, since carnitine behaves as a shuttle for acetyl groups from inside to outside the mitochondrial membrane, it covers also a key role in glucose metabolism and assists in fuel‐sensing. A reduction of the fatty acid transport inside the mitochondria results in the cytosolic accumulation of triglycerides, which is implicated in the pathogenesis of insulin resistance. Acute hypercarnitinemia stimulates nonoxidative glucose disposal during euglycemic hyperinsulinemic clamp in healthy volunteers. Similar results were obtained in type 2 diabetic patients. The above findings were confirmed in healthy volunteers using the minimal modeling of glucose kinetics. The total end‐clamp glucose tissue uptake was significantly increased by the administration of doses of acetyl‐l‐carnitine (ALC) from 3.8 to 5.2 mg/kg/min, without a significant dose‐response effect. In conclusion, both l‐carnitine and ALC are effective in improving insulin‐mediated glucose disposal either in healthy subjects or in type 2 diabetic patients. Two possible mechanisms might be invoked in the metabolic effect of carnitine and its derivative: the first is a regulation of acetyl and acyl cellular trafficking for correctly meeting the energy demand; the second is a control action in the synthesis of key glycolytic and gluconeogenic enzymes.
Delaying the Mitochondrial Decay of Aging with Acetylcarnitine
Authors: AMES BRUCE N. , LIU JIANKANG
Published: December 2004

Abstract: Oxidative mitochondrial decay is a major contributor to aging. Some of this decay can be reversed in old rats by feeding them normal mitochondrial metabolites, acetylcarnitine (ALC) and lipoic acid (LA), at high levels. Feeding the substrate ALC with LA, a mitochondrial antioxidant, restores the velocity of the reaction (Km) for ALC transferase and mitochondrial function. The principle appears to be that, with age, increased oxidative damage to protein causes a deformation of structure of key enzymes with a consequent lessening of affinity (Km) for the enzyme substrate. The effect of age on the enzyme‐binding affinity can be mimicked by reacting it with malondialdehyde (a lipid peroxidation product that increases with age). In old rats (vs. young rats), mitochondrial membrane potential, cardiolipin level, respiratory control ratio, and cellular O2 uptake are lower; oxidants/O2, neuron RNA oxidation, and mutagenic aldehydes from lipid peroxidation are higher. Ambulatory activity and cognition decline with age. Feeding old rats ALC with LA for a few weeks restores mitochondrial function; lowers oxidants, neuron RNA oxidation, and mutagenic aldehydes; and increases rat ambulatory activity and cognition (as assayed with the Skinner box and Morris water maze). A recent meta‐analysis of 21 double‐blind clinical trials of ALC in the treatment of mild cognitive impairment and mild Alzheimer's disease showed significant efficacy vs. placebo. A meta‐analysis of 4 clinical trials of LA for treatment of neuropathic deficits in diabetes showed significant efficacy vs. placebo.
Comparison of the Effects of l‐Carnitine and Acetyl‐l‐Carnitine on Carnitine Levels, Ambulatory Activity, and Oxidative Stress Biomarkers in the Brain of Old Rats
Authors: LIU JIANKANG , HEAD ELIZABETH , KURATSUNE HIROHIKO , COTMAN CARL W. , AMES BRUCE N.
Published: December 2004

Abstract: l‐Carnitine and acetyl‐l‐carnitine (ALC) are both used to improve mitochondrial function. Although it has been argued that ALC is better than l‐carnitine in absorption and activity, there has been no experiment to compare the two compounds at the same dose. In the present experiment, the effects of ALC and l‐carnitine on the levels of free, acyl, and total l‐carnitine in plasma and brain, rat ambulatory activity, and biomarkers of oxidative stress are investigated. Aged rats (23 months old) were given ALC or l‐carnitine at 0.15% in drinking water for 4 weeks. l‐Carnitine and ALC were similar in elevating carnitine levels in plasma and brain. Both increased ambulatory activity similarly. However, ALC decreased the lipid peroxidation (malondialdehyde, MDA) in the old rat brain, while l‐carnitine did not. ALC decreased the extent of oxidized nucleotides (oxo8dG/oxo8G) immunostaining in the hippocampal CA1 and cortex, while l‐carnitine did not. ALC decreased nitrotyrosine immunostaining in the hippocampal CA1 and white matter, while l‐carnitine did not. In conclusion, ALC and l‐carnitine were similar in increasing ambulatory activity in old rats and elevating carnitine levels in blood and brain. However, ALC was effective, unlike l‐carnitine, in decreasing oxidative damage, including MDA, oxo8dG/oxo8G, and nitrotyrosine, in old rat brain. These data suggest that ALC may be a better dietary supplement than l‐carnitine.
Carnitines and Its Congeners: A Metabolic Pathway to the Regulation of Immune Response and Inflammation
Authors: FAMULARO GIUSEPPE , de SIMONE CLAUDIO , TRINCHIERI VITO , MOSCA LUCIANA
Published: December 2004

Abstract: Carnitine and its congeners may regulate the immune networks, and their influence on functions of immune cells predominantly or exclusively relies on carnitine‐dependent energy production from fatty acids. A reduced pool of carnitines has been demonstrated in either serum or tissues, or both, from patients with a wide spectrum of disorders characterized by unregulated or impaired immune responses ranging from sepsis syndrome to systemic sclerosis, infection with human immunodeficiency virus, and chronic fatigue syndrome. Furthermore, experimental studies have consistently reported that the deranged immune responses and the less efficient inflammation towards infectious organisms associated with aging may be enhanced or modulated by treatment with carnitines. There is also evidence that carnitine deprivation could adversely affect the course of the sepsis syndrome, at least in experimental models, and preliminary studies suggest that carnitine deficiency is ultimately implicated in the pathophysiology of endotoxin‐mediated multiple organ failure. Several data indicate that carnitine deficiency is a contributing factor to the progression of infection with human immunodeficiency virus, and carnitine therapy in those patients could counteract the unregulated process of lymphocyte apoptosis and improve CD4 counts. Some case reports have suggested the use of carnitine for the treatment of the severe lactic acidosis that complicates in some patients the use of reverse transcriptase inhibitors.
l‐Carnitine Supplementation for the Treatment of Fatigue and Depressed Mood in Cancer Patients with Carnitine Deficiency: A Preliminary Analysis
Authors: CRUCIANI R A , DVORKIN E , HOMEL P , CULLINEY B , MALAMUD S , SHAIOVA L , FLEISHMAN S , LAPIN J , KLEIN E , LESAGE P , PORTENOY R , ESTEBAN‐CRUCIANI N
Published: December 2004

Abstract: Nutritional factors are among the postulated causes of fatigue, a highly prevalent symptom in the cancer population, with serious impact on patients’ quality of life. Deficiency of the micronutrient carnitine may play a role by reducing energy production through fatty acid oxidation. We present preliminary data of an open‐label, dose‐finding study to determine safety and maximally tolerated dose (MTD) of 1 week of l‐carnitine supplementation in cancer patients with fatigue and carnitine deficiency. Patients who met inclusion/exclusion criteria underwent carnitine level determination. Eighty‐three percent of these patients (15/18) had carnitine deficiency. Preliminary data analysis of 13 patients showed that total carnitine increased from 30.0 ± 6.9 to 41.0 ± 12.1 (mean ± SD) after 1 week of supplementation (P= 0.01), and free carnitine increased from 24.3 ± 6.1 to 33.8 ± 9.8 (P= 0.004). Outcome measures were fatigue (BFI score), depression (CES‐D), sleep disruption (ESS), and performance status (Karnofsky). Median (min, max) BFI score at baseline was 73 (46, 82) versus 50 (3, 82) after 1‐week supplementation (P= 0.009). CES‐D score at baseline was 29 (16, 42) and 22 (8, 32) after 1 week (P= 0.028). ESS at baseline was 46.5 (0, 69) and 30.4 (0, 72) after 1 week (P= 0.015). Karnofsky score did not change significantly (P= 0.38). We are currently conducting a randomized, double‐blind, placebo‐controlled study to rigorously assess the role of l‐carnitine for the treatment of fatigue and depression in cancer patients.
l‐Carnitine May Attenuate Free Fatty Acid‐Induced Endothelial Dysfunction
Authors: SHANKAR SUDHA S. , MIRZAMOHAMMADI BAHRAM , WALSH JAMES P. , STEINBERG HELMUT O.
Published: December 2004

Abstract: We have recently shown that elevated levels of free fatty acid (FFA) seen in insulin‐resistant obese subjects are associated with endothelial dysfunction. l‐Carnitine, which is required for mitochondrial FFA transport/oxidation, has been reported to improve vascular function in subjects with diabetes and heart disease. Here, we tested the hypothesis that l‐carnitine attenuates FFA‐induced endothelial dysfunction. We studied leg blood flow (LBF) responses and leg vascular resistance (LVR) to graded intrafemoral artery infusions of the endothelium‐dependent vasodilator, methacholine chloride (MCh). A group (n= 7) of normal lean subjects was studied under basal conditions (saline), after 2 h of FFA elevation (FFA), and then after 2 h of superimposing l‐carnitine on FFA elevation. FFA elevation caused the maximal LBF increment in response to MCh to decrease from 0.388 ± 0.08 to 0.212 ± 0.071 L/min (P= 0.05). Similarly, FFA blunted the maximum decrease in LVR in response to MCh from −315 ± 41 U to −105 ± 46 U (P= 0.05). The superimposed l‐carnitine restored the LBF increment in response to MCh to 0.488 ± 0.088 L/min (P= 0.05 vs. FFA) and the maximum fall in LVR to −287 ± 75 U (P= 0.05 vs. FFA), indicating that l‐carnitine elevation may attenuate FFA‐induced endothelial dysfunction. In conclusion, our data suggest that increasing l‐carnitine levels may improve FFA‐induced and obesity‐associated endothelial dysfunction. This improved endothelial function may delay or prevent the development of excess cardiovascular disease.
Signaling circuitries in development: insights from the retinal determination gene network
Authors: Silver Serena J. , Rebay Ilaria
Published: December 2004

Context-specific integration of information received from the Notch,Transforming growth factor β, Wingless/Wnt, Hedgehog and Epidermal growth factor receptor signaling pathways sets the stage for deployment of the retinal determination gene network (RDGN), a group of transcription factors that collectively directs the formation of the eye and other tissues. Recent investigations have revealed how these transcription factors are regulated by their interactions with each other and with effectors of the above signaling pathways. Further study of the RDGN may provide insights into how common cues can generate context-specific responses, a key aspect of developmental regulation that remains poorly understood.
Interaction of 14-3-3 protein with Chk1 affects localization and checkpoint function
Authors: Dunaway Stephen , Liu Hsing-Yin , Walworth Nancy C.
Published: December 2004

The protein kinase Chk1 is required for proper arrest of the cell cycle in response to DNA damage. We have previously shown in Schizosaccharomyces pombe, that upon DNA damage, phosphorylation of Chk1 correlates with checkpoint activation and that phosphorylated Chk1 is capable of interacting with the 14-3-3 proteins, Rad24 and Rad25. The interaction between Rad24 and Chk1 is stimulated tenfold after exposure to DNA damaging agents and we postulate that it is an important event in the DNA damage checkpoint response pathway in fission yeast. We identified a stretch of leucine residues as the domain in Chk1 that mediates the interaction with 14-3-3 proteins. Substitution of leucine residues with alanine disrupts the interaction with Rad24 and also prevents Chk1 from becoming phosphorylated in response to DNA damaging agents. Cells expressing the mutants are sensitive to UV radiation. In this study, we also show that Chk1 accumulates in the nucleus in response to DNA damage and this behavior is dependent on Rad24. Interestingly, the 14-3-3 binding domain mutants also fail to localize to the nucleus prompting a search for localization sequences within Chk1. Our investigations have identified the presence of both functional nuclear import and nuclear export sequences encoded in S. pombe Chk1 that, in conjunction with 14-3-3 proteins, may play a prominent role in regulating Chk1 localization and function.
Interplay between paracrine signaling and gap junctional communication in ovarian follicles
Authors: Gittens Joanne E. I. , Barr Kevin J. , Vanderhyden Barbara C. , Kidder Gerald M.
Published: December 2004

Intercellular communication is required for ovarian folliculogenesis. This is apparent in mice lacking connexin43 (Cx43, a gap junction protein strongly expressed in granulosa cells), or growth/differentiation factor-9 (GDF9, an oocyte-specific growth factor that stimulates granulosa cell proliferation and differentiation), or in mice expressing a mutant form of Kit ligand (KITL, a paracrine factor that, in the ovary, is secreted by granulosa cells to stimulate oocyte growth). In all of these mutant lines, follicle growth is impaired suggesting a possible interaction between paracrine signaling and gap junctional communication. To assess this possibility, we analyzed gene expression in mutant ovaries. Despite the lack of gap junctional coupling between granulosa cells of Cx43 null mutant ovaries, expression of the genes encoding KITL and its receptor, KIT, is maintained. Furthermore, GDF9 expression is maintained. In GDF9 null mutant ovaries, there is no apparent change in Cx43 expression and, correspondingly, the granulosa cells remain coupled. There is also no increase in granulosa cell apoptosis in ovaries lacking Cx43 or GDF9. Staining for proliferating cell nuclear antigen (PCNA) revealed that the granulosa cells of Cx43 null mutant ovaries have a reduced frequency of DNA synthesis. Using both radiolabeled thymidine incorporation and PCNA staining in vitro, we showed that recombinant GDF9 could restore the proliferation of coupling-deficient granulosa cells to the level of control cells. These results indicate that impaired folliculogenesis in mice lacking Cx43 is due at least in part to reduced responsiveness of granulosa cells to oocyte-derived GDF9, indicating an interaction between these two modes of intercellular communication.
Ciz1 promotes mammalian DNA replication
Authors: Coverley Dawn , Marr Jackie , Ainscough Justin
Published: December 2004

Using a cell-free system that reconstitutes initiation of mammalian DNA replication, we identified a cyclin A-responsive protein, p21Cip1-interacting zinc finger protein 1 (Ciz1). In cell-free experiments, Ciz1 protein increases the number of nuclei that initiate DNA replication, and in intact cells GFP-tagged Ciz1 stimulates DNA synthesis, in both a wild-type and a p21Cip1 null background. Furthermore, mutation of a putative cyclin-dependent kinase phosphorylation site at threonines 191/2 alters Ciz1 activity in vitro, indicating that this site plays a role in regulating Ciz1. Consistent with a role in DNA replication, endogenous Ciz1 is present in nuclear foci that co-localize with PCNA during S phase, and targeted depletion of Ciz1 transcripts restrains cell proliferation by inhibiting entry to S phase. Ciz1-depleted cells accumulate with chromatin bound Mcm3 and PCNA but fail to synthesize DNA efficiently. These cell-based and cell-free experiments suggest that Ciz1 functions to promote DNA replication after replication complex formation. Finally, alternatively spliced forms of Ciz1 occur in embryonic cells from mouse and man, raising the possibility that Ciz1 splicing contributes to the regulation of DNA replication during development.