bluuebunny/crossref_metadata_2025 huggingface dataset:
A "Gap Bridger"
Authors: Rashid Richard
Published: June 2008

I knew Jim Gray as a colleague, a friend and an employee. He created the first Microsoft Research group outside of our initial research lab in Redmond, WA. Jim's impact on industry and science was not limited to his own area of research. He championed new ways of thinking about how computer science and information processing could be integrated into other areas of research. In so doing; he will have a lasting impact on the rate of progress in many disciplines. His success stemmed not just from what he knew and what he could do with his knowledge, but also from who he was as a person. Jim was a "Gap Bridger" -- someone who could connect people, groups, companies and disciplines.
Jim Gray at IBM
Authors: Lindsay Bruce G.
Published: June 2008

While at the IBM San Jose Research Laboratory, in the 1970's, Dr. Jim Gray defined and developed the fundamental concepts and techniques that underlie on-line transaction processing systems. Jim Gray's pivotal contributions enabled cost efficient, on-line processing to replace paper and batch processing systems. Today, online transaction processing powers the record keeping systems that drive today's commerce, services, and government.
Jim Gray's Tandem contributions
Authors: Nauman John , Bartlett Wendy
Published: June 2008

This paper discusses the contributions and accomplishments of Jim Gray while he was at Tandem Computers between 1980 and the early 1990s.
Not just correct, but correct and fast
Authors: DeWitt David J. , Levine Charles
Published: June 2008

This paper examines Jim Gray's role in the specification of the debit/credit benchmark. The publication of this benchmark in a 1985 paper launched a benchmark war among the vendors that resulted in dramatic improvements in database system performance in the years following its publication. It was the genesis of the TPC, an industry consortium which has reshaped the benchmark landscape. Descendents of this benchmark continue to this day to be an important metric of modern transaction processing systems.
Scaleability and immortality
Authors: Bell C Gordon
Published: June 2008

James Nicholas Gray's understanding and experimentation gave him a special perspective. From 1995 his commitment was building indefinitely scalable tools by working on really hard data-intensive application problems with other scientific disciplines. His attention to research for both understanding and use made him a unique researcher. Jim pioneered a new kind of 21
st
century science based on data analytics, requiring computer scientists to collaborate as an equal with scientists in other fields.

Gray was an advocate and principal supporter of the MyLifeBits project aimed at extending our memory, memex. The by-product includes digital immortality that we herein speculate and explore.
Is there life outside transactions?
Authors: Reuter Andreas
Published: June 2008

In this article I will reflect on the writing of "Transaction Processing -- Concepts and Techniques" [1], which appeared at Morgan Kaufmann Publishers in 1992. The process of writing had many aspects of a typical software project: In the end, the book was more than twice as thick as we had planned, it covered only 3/4 of the material that we wanted to cover, and completing it took much longer than we had anticipated. Nevertheless, it was a moderate success and served as a basic reference for many developers in the industry for at least 10 years after its publication. It was translated to Chinese and Japanese, and occasionally one still finds references to it -- despite the fact that (apart from simple bug fixes) there has been no technical update of the material, and the book deals with "outdated" subjects like transaction processing and client/server architectures.
TerraServer and the Russia adventure...
Authors: Barclay Tom
Published: June 2008

Jim Gray made many friends and few enemies in his career. Many of the projects he worked on were inspired by one or more of his friends and collaborators in industry and academia.

The original idea for an "image server" happened in the early 1990s when Jim was at Digital. Jim had met Jeff Dozier while working on the National Research Council's "Computing the Future" committee [NRC 1994]. Jeff became Dean of the Bren School of Environmental Sciences and chair of UC Santa Barbara's Alexandria Digital Library advisory board. Jeff asked Jim to serve on the board.

During an Alexandria board meeting, Jeff and Jim discussed the idea for a "geospatial image server". All they needed was a lot of accessible imagery, someone that wanted it done, and someone foolish enough to load a few tera-bytes of data. The cold war ended enabling the high resolution imagery marketplace. Microsoft SQL Server wanted a scalability internet demonstration. And I walked into Jim Gray's lab looking for a reason to move back to San Francisco. And that's where my 10 year project with Jim Gray and TerraServer begins...
The Sloan Digital Sky Survey and beyond
Authors: Szalay Alexander S.
Published: June 2008

Our collaboration with Jim Gray has created some of the world's largest astronomy databases, and has enabled us to test many avant-garde ideas in practice. The astronomers have been very receptive to these and embraced Jim as a 'card carrying member' of their community. Jim's contributions have made a permanent mark on astronomy, and eScience in general.
Building the WorldWide Telescope
Authors: Wong Curtis
Published: June 2008

This paper is talks about the critical role that Jim Gray played in the creation of the WorldWide Telescope software. Contrary to what you might think it wasn't his database brilliance that made it happen, it was his generosity in sharing credit, inspiring, nurturing and connecting people, in this case that made it possible for the pieces to come into place and make it happen. Without Jim Gray's work with Alex Szalay on Sky Server and their ongoing support and encouragement, the software that is named in their honor would not exist today.
Search survey for S/V Tenacious
Authors: Saade Ed
Published: June 2008

On January 28
th
, 2007, Jim Gray sailed his 40 foot sailboat, Tenacious, on a day cruise to the Farallon Islands off San Francisco and was reported overdue when he didn't return as scheduled. The immediate and comprehensive above water search for Jim and Tenacious was suspended on February 16, 2007. Shortly after this, Fugro Pelagos, Inc., conducted an extensive search of the seabed to look for evidence of the whereabouts of the sailing vessel, Tenacious. Approximately 1000km
2
was surveyed between February, 2007 and May 31
st
, 2007 when the effort was suspended.

This paper summarizes the search survey for S/V Tenacious, the areas and techniques used in the survey, the findings of the survey, and the results and recommendations provided by Fugro Pelagos, Inc.
Habits, Rituals, and the Evaluative Brain
Authors: Graybiel Ann M.
Published: June 2008

Scientists in many different fields have been attracted to the study of habits because of the power habits have over behavior and because they invoke a dichotomy between the conscious, voluntary control over behavior, considered the essence of higher-order deliberative behavioral control, and lower-order behavioral control that is scarcely available to consciousness. A broad spectrum of behavioral routines and rituals can become habitual and stereotyped through learning. Others have a strong innate basis. Repetitive behaviors can also appear as cardinal symptoms in a broad range of neurological and neuropsychiatric illness and in addictive states. This review suggests that many of these behaviors could emerge as a result of experience-dependent plasticity in basal ganglia–based circuits that can influence not only overt behaviors but also cognitive activity. Culturally based rituals may reflect privileged interactions between the basal ganglia and cortically based circuits that influence social, emotional, and action functions of the brain.
Mechanisms of Self-Motion Perception
Authors: Britten Kenneth H.
Published: June 2008

Guiding effective movement through the environment is one of the visual system's most important functions. The pattern of motion that we see allows us to estimate our heading accurately in a variety of environments, despite the added difficulty imposed by our own eye and head movements. The cortical substrates for heading perception include the medial superior temporal area (MST) and the ventral intraparietal area (VIP). This review discusses recent work on these two areas in the context of behavioral observations that establish the important problems the visual system must solve. Signals relevant to self motion are both more widespread than heretofore recognized and also more complex because they are multiplexed with other sensory signals, such as vestibular, auditory, and tactile information. The review presents recent work as a background to highlight important problems that remain unsolved.
Mechanisms of Face Perception
Authors: Tsao Doris Y. , Livingstone Margaret S.
Published: June 2008

Faces are among the most informative stimuli we ever perceive: Even a split-second glimpse of a person's face tells us his identity, sex, mood, age, race, and direction of attention. The specialness of face processing is acknowledged in the artificial vision community, where contests for face-recognition algorithms abound. Neurological evidence strongly implicates a dedicated machinery for face processing in the human brain to explain the double dissociability of face- and object-recognition deficits. Furthermore, recent evidence shows that macaques too have specialized neural machinery for processing faces. Here we propose a unifying hypothesis, deduced from computational, neurological, fMRI, and single-unit experiments: that what makes face processing special is that it is gated by an obligatory detection process. We clarify this idea in concrete algorithmic terms and show how it can explain a variety of phenomena associated with face processing.
Axon-Glial Signaling and the Glial Support of Axon Function
Authors: Nave Klaus-Armin , Trapp Bruce D.
Published: June 2008

Oligodendrocytes and Schwann cells are highly specialized glial cells that wrap axons with a multilayered myelin membrane for rapid impulse conduction. Investigators have recently identified axonal signals that recruit myelin-forming Schwann cells from an alternate fate of simple axonal engulfment. This is the evolutionary oldest form of axon-glia interaction, and its function is unknown. Recent observations suggest that oligodendrocytes and Schwann cells not only myelinate axons but also maintain their long-term functional integrity. Mutations in the mouse reveal that axonal support by oligodendrocytes is independent of myelin assembly. The underlying mechanisms are still poorly understood; we do know that to maintain axonal integrity, mammalian myelin-forming cells require the expression of some glia-specific proteins, including CNP, PLP, and MAG, as well as intact peroxisomes, none of which is necessary for myelin assembly. Loss of glial support causes progressive axon degeneration and possibly local inflammation, both of which are likely to contribute to a variety of neuronal diseases in the central and peripheral nervous systems.
Multiple Sclerosis: An Immune or Neurodegenerative Disorder?
Authors: Trapp Bruce D. , Nave Klaus-Armin
Published: June 2008

Multiple sclerosis (MS) is an inflammatory-mediated demyelinating disease of the human central nervous system. The clinical disease course is variable, usually starts with reversible episodes of neurological disability in the third or fourth decade of life, and transforms into a disease of continuous and irreversible neurological decline by the sixth or seventh decade. We review data that support neurodegeneration as the major cause of irreversible neurological disability in MS patients. We question whether inflammatory demyelination is primary or secondary in the disease process and discuss the challenges of elucidating the cause of MS and developing therapies that will delay or prevent the irreversible and progressive neurological decline that most MS patients endure.
Neural Substrates of Language Acquisition
Authors: Kuhl Patricia , Rivera-Gaxiola Maritza
Published: June 2008

Infants learn language(s) with apparent ease, and the tools of modern neuroscience are providing valuable information about the mechanisms that underlie this capacity. Noninvasive, safe brain technologies have now been proven feasible for use with children starting at birth. The past decade has produced an explosion in neuroscience research examining young children's processing of language at the phonetic, word, and sentence levels. At all levels of language, the neural signatures of learning can be documented at remarkably early points in development. Individual continuity in linguistic development from infants' earliest responses to phonemes is reflected in infants' language abilities in the second and third year of life, a finding with theoretical and clinical implications. Developmental neuroscience studies using language are beginning to answer questions about the origins of humans' language faculty.
Mechanisms Underlying Development of Visual Maps and Receptive Fields
Authors: Huberman Andrew D. , Feller Marla B. , Chapman Barbara
Published: June 2008

Patterns of synaptic connections in the visual system are remarkably precise. These connections dictate the receptive field properties of individual visual neurons and ultimately determine the quality of visual perception. Spontaneous neural activity is necessary for the development of various receptive field properties and visual feature maps. In recent years, attention has shifted to understanding the mechanisms by which spontaneous activity in the developing retina, lateral geniculate nucleus, and visual cortex instruct the axonal and dendritic refinements that give rise to orderly connections in the visual system. Axon guidance cues and a growing list of other molecules, including immune system factors, have also recently been implicated in visual circuit wiring. A major goal now is to determine how these molecules cooperate with spontaneous and visually evoked activity to give rise to the circuits underlying precise receptive field tuning and orderly visual maps.
Descending Pathways in Motor Control
Authors: Lemon Roger N.
Published: June 2008

Each of the descending pathways involved in motor control has a number of anatomical, molecular, pharmacological, and neuroinformatic characteristics. They are differentially involved in motor control, a process that results from operations involving the entire motor network rather than from the brain commanding the spinal cord. A given pathway can have many functional roles. This review explores to what extent descending pathways are highly conserved across species and concludes that there are actually rather widespread species differences, for example, in the transmission of information from the corticospinal tract to upper limb motoneurons. The significance of direct, cortico-motoneuronal (CM) connections, which were discovered a little more than 50 years ago, is reassessed. I conclude that although these connections operate in parallel with other less direct linkages to motoneurons, CM influence is significant and may subserve some special functions including adaptive motor behaviors involving the distal extremities.
Multifunctional Pattern-Generating Circuits
Authors: Briggman K.L. , Kristan W.B.
Published: June 2008

The ability of distinct anatomical circuits to generate multiple behavioral patterns is widespread among vertebrate and invertebrate species. These multifunctional neuronal circuits are the result of multistable neural dynamics and modular organization. The evidence suggests multifunctional circuits can be classified by distinct architectures, yet the activity patterns of individual neurons involved in more than one behavior can vary dramatically. Several mechanisms, including sensory input, the parallel activity of projection neurons, neuromodulation, and biomechanics, are responsible for the switching between patterns. Recent advances in both analytical and experimental tools have aided the study of these complex circuits.
Retinal Axon Growth at the Optic Chiasm: To Cross or Not to Cross
Authors: Petros Timothy J. , Rebsam Alexandra , Mason Carol A.
Published: June 2008

At the optic chiasm, retinal ganglion cell axons from each eye converge and segregate into crossed and uncrossed projections, a pattern critical for binocular vision. Here, we review recent findings on optic chiasm development, highlighting the specific transcription factors and guidance cues that implement retinal axon divergence into crossed and uncrossed pathways. Although mechanisms underlying the formation of the uncrossed projection have been identified, the means by which retinal axons are guided across the midline are still unclear. In addition to directives provided by transcription factors and receptors in the retina, gene expression in the ventral diencephalon influences chiasm formation. Throughout this review, we compare guidance mechanisms at the optic chiasm with those in other midline models and highlight unanswered questions both for retinal axon growth and axon guidance in general.
The Prion's Elusive Reason for Being
Authors: Aguzzi Adriano , Baumann Frank , Bremer Juliane
Published: June 2008

The protein-only hypothesis posits that the infectious agent causing transmissible spongiform encephalopathies consists of protein and lacks any informational nucleic acids. This agent, termed prion by Stanley Prusiner, is thought to consist partly of PrPSc, a conformational isoform of a normal cellular protein termed PrPC. Scientists and lay persons have been fascinated by the prion concept, and it has been subjected to passionate critique and intense experimental scrutiny. As a result, PrPC and its isoforms rank among the most intensively studied proteins encoded by the mammalian genome. Despite all this research, both the physiological function of PrPC and the molecular pathways leading to neurodegeneration in prion disease remain unknown. Here we review the salient traits of those diseases ascribed to improper behavior of the prion protein and highlight how the physiological functions of PrPC may help explain the toxic phenotypes observed in prion disease.
Brain Circuits for the Internal Monitoring of Movements
Authors: Sommer Marc A. , Wurtz Robert H.
Published: June 2008

Each movement we make activates our own sensory receptors, thus causing a problem for the brain: the spurious, movement-related sensations must be discriminated from the sensory inputs that really matter, those representing our environment. Here we consider circuits for solving this problem in the primate brain. Such circuits convey a copy of each motor command, known as a corollary discharge (CD), to brain regions that use sensory input. In the visual system, CD signals may help to produce a stable visual percept from the jumpy images resulting from our rapid eye movements. A candidate pathway for providing CD for vision ascends from the superior colliculus to the frontal cortex in the primate brain. This circuit conveys warning signals about impending eye movements that are used for planning subsequent movements and analyzing the visual world. Identifying this circuit has provided a model for studying CD in other primate sensory systems and may lead to a better understanding of motor and mental disorders.
Signaling Mechanisms Linking Neuronal Activity to Gene Expression and Plasticity of the Nervous System
Authors: Flavell Steven W. , Greenberg Michael E.
Published: June 2008

Sensory experience and the resulting synaptic activity within the brain are critical for the proper development of neural circuits. Experience-driven synaptic activity causes membrane depolarization and calcium influx into select neurons within a neural circuit, which in turn trigger a wide variety of cellular changes that alter the synaptic connectivity within the neural circuit. One way in which calcium influx leads to the remodeling of synapses made by neurons is through the activation of new gene transcription. Recent studies have identified many of the signaling pathways that link neuronal activity to transcription, revealing both the transcription factors that mediate this process and the neuronal activity–regulated genes. These studies indicate that neuronal activity regulates a complex program of gene expression involved in many aspects of neuronal development, including dendritic branching, synapse maturation, and synapse elimination. Genetic mutations in several key regulators of activity-dependent transcription give rise to neurological disorders in humans, suggesting that future studies of this gene expression program will likely provide insight into the mechanisms by which the disruption of proper synapse development can give rise to a variety of neurological disorders.
Task Set and Prefrontal Cortex
Authors: Sakai Katsuyuki
Published: June 2008

A task set is a configuration of cognitive processes that is actively maintained for subsequent task performance. Single-unit and brain-imaging studies have identified the neural correlates for task sets in the prefrontal cortex. Here I examine whether the neural data obtained thus far are sufficient to explain the behaviors that have been illustrated within the conceptual framework of task sets. I first discuss the selectivity of neural activity in representing a specific task. I then discuss the competitions between neural representations of task sets during task switch. Finally I discuss how, in neural terms, a task set is implemented to facilitate task performance. The processes of representing, updating, and implementing task sets occur in parallel at multiple levels of brain organization. Neural accounts of task sets demonstrate that the brain determines our thoughts and behaviors.
Wnt Signaling in Neural Circuit Assembly
Authors: Salinas Patricia C. , Zou Yimin
Published: June 2008

The Wnt family of secreted proteins plays a crucial role in nervous system wiring. Wnts regulate neuronal positioning, polarization, axon and dendrite development, and synaptogenesis. These diverse roles of Wnt proteins are due not only to the large numbers of Wnt ligands and receptors but also to their ability to signal through distinct signaling pathways in different cell types and developmental contexts. Studies on Wnts have shed new light on novel molecular mechanisms that control the development of complex neuronal connections. This review discusses recent advances on how Wnt signaling influences different aspects of neuronal circuit assembly through changes in gene expression and/or cytoskeletal modulation.
Role of Axonal Transport in Neurodegenerative Diseases
Authors: De Vos Kurt J. , Grierson Andrew J. , Ackerley Steven , Miller Christopher C.J.
Published: June 2008

Many major human neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis (ALS), display axonal pathologies including abnormal accumulations of proteins and organelles. Such pathologies highlight damage to the axon as part of the pathogenic process and, in particular, damage to transport of cargoes through axons. Indeed, we now know that disruption of axonal transport is an early and perhaps causative event in many of these diseases. Here, we review the role of axonal transport in neurodegenerative disease.
Effects of arecoline on testosterone release in rats
Authors: Wang Shyi-Wu , Hwang Guey-Shyang , Chen Te-Jung , Wang Paulus S.
Published: June 2008

Arecoline is one of the major components of betel nuts, which have been consumed as chewing gum in Southeast Asia. In this study, the effects of arecoline on testosterone (T) secretion were explored. Male rats were injected with human chorionic gonadotropin (hCG, 5 IU/kg) or arecoline (1 μg/kg) plus hCG via a jugular catheter. Blood samples were collected at several time intervals subsequent to the challenge. Rat anterior pituitary was treated with gonadotropin-releasing hormone in vitro with or without arecoline, and then the concentration s of luteinizing hormone (LH) in the medium were measured. Rat Leydig cells were purified by Percoll density gradient centrifugation and incubated with arecoline, hCG, forskolin, 8-bromo-cAMP (8-Br-cAMP), nifedipine, nimodipine, or tetrandrine at 34°C for 1 h. A single intravenous injection of arecoline resulted in an increase of the hCG-induced level of plasma T. Administration of arecoline (10−8 to 10−6 M) in vitro increased T production in Leydig cells. The stimulatory effect of arecoline on T release in vitro was enhanced by hCG (0.001 IU/ml), forskolin (10−6 M), or 8-Br-cAMP (10−5 M). By contrast, nifedipine, nimodipine, or tetrandrine inhibited the increased T concentrations induced by arecoline. Western blot showed that arecoline increases steroidogenic acute regulatory (StAR) protein expression compared with vehicle. These results suggested that arecoline stimulates testosterone production by acting directly on Leydig cells via mechanisms involving an activation of L-type calcium channels, increasing the activity of 17β-hydroxysteroid dehydrogenase and enhancing the expression of StAR.
Microarray analyses of SREBP-1a and SREBP-1c target genes identify new regulatory pathways in muscle
Authors: Rome Sophie , Lecomte Virginie , Meugnier Emmanuelle , Rieusset Jennifer , Debard Cyrille , Euthine Vanessa , Vidal Hubert , Lefai Etienne
Published: June 2008

In this study we have identified the target genes of sterol regulatory element binding protein (SREBP)-1a and SREBP-1c in primary cultures of human skeletal muscle cells, using adenoviral vectors expressing the mature nuclear form of human SREBP-1a or SREBP-1c combined with oligonucleotide microarrays. Overexpression of SREBP-1a led to significant changes in the expression of 1,315 genes (655 upregulated and 660 downregulated), whereas overexpression of SREBP-1c modified the mRNA level of 514 genes (310 upregulated and 204 downregulated). Gene ontology analysis indicated that in human muscle cells SREBP-1a and -1c are involved in the regulation of a large number of genes that are at the crossroads of different functional pathways, several of which are not directly connected with cholesterol and lipid metabolism. Six hundred fifty-two of all genes identified to be differentially regulated on SREBP overexpression had a sterol regulatory element (SRE) motif in their promoter sequences. Among these, 429 were specifically regulated by SREBP-1a, 69 by SREBP-1c, and 154 by both 1a and 1c. Because both isoforms recognize the same binding motif, we determined whether some of these functional differences could depend on the environment of the SRE motifs in the promoters. Results from promoter analysis showed that different combinations of transcription factor binding sites around the SRE binding motifs may determine regulatory networks of transcription that could explain the superposition of lipid and cholesterol metabolism with various other pathways involved in adaptive responses to stress like hypoxia and heat shock, or involvement in the immune response.
Towards an Information Model of Consistency Maintenance in Distributed Interactive Applications
Authors: Zhang Xin , Ward Tomás E. , McLoone Séamus
Published: June 2008

A novel framework to model and explore predictive contract mechanisms in distributed interactive applications (DIAs) using information theory is proposed. In our model, the entity state update scheme is modelled as an information generation, encoding, and reconstruction process. Such a perspective facilitates a quantitative measurement of state fidelity loss as a result of the distribution protocol. Results from an experimental study on a first‐person shooter game are used to illustrate the utility of this measurement process. We contend that our proposed model is a starting point to reframe and analyse consistency maintenance in DIAs as a problem in distributed interactive media compression.
Argatroban Anticoagulation in Renal Dysfunction: A Literature Analysis
Authors: Hursting Marcie J. , Murray Patrick T.
Published: June 2008

Background/Aims: Argatroban, a hepatically metabolized direct thrombin inhibitor, is approved for use in heparin-induced thrombocytopenia (HIT; several countries) and in antithrombin-deficient patients undergoing hemodialysis (Japan). This literature analysis aimed to determine the effects of renal function on argatroban pharmacokinetics, pharmacodynamics, and its therapeutic dose in HIT and to evaluate argatroban dosing and safety during renal replacement therapy (RRT) and in adults with renal dysfunction undergoing surgical or invasive procedures. Methods: A literature search identified 34 publications (12 prospective studies, 4 retrospective studies, 18 anecdotal reports) that together described 644 argatroban-treated patients (446 with HIT, 82 with antithrombin deficiency) with varying degrees of renal function. Pertinent data were extracted and summarized. Results: In pharmacokinetic studies (40 patients, overall), renal dysfunction exerted little or no clinically significant effects on argatroban pharmacokinetic parameters. For argatroban therapy in HIT, evidence existed that an initial 2 µg/kg/min dose was sometimes excessive; patients with hepatic dysfunction, irrespective of renal function, required reduced initial doses; lesser doses were required in combined hepatic and renal dysfunction than hepatic dysfunction, and for each 30 ml/min decrease in patient creatinine clearance, the therapeutic dose decreased ∼0.1–0.6 µg/kg/min. Argatroban was well tolerated and enabled RRT with little or no thrombotic or hemorrhagic complications. Experiences with argatroban in renally impaired patients undergoing procedures besides RRT were limited. Conclusion: Current literature suggests that argatroban is well tolerated and provides adequate anticoagulation in patients with renal dysfunction or failure, including individuals with HIT or antithrombin deficiency where anticoagulant options are limited.
Application of Microemulsions in Dermal and Transdermal Drug Delivery
Authors: Santos P. , Watkinson A.C. , Hadgraft J. , Lane M.E.
Published: June 2008

Microemulsions are thermodynamically stable colloidal dispersions of water and oil stabilized by a surfactant and, in many cases, also a cosurfactant. In the pharmaceutical field, microemulsions have been used as drug carriers for percutaneous, ocular, oral and parenteral administration. This review discusses some of the applications of microemulsions specifically for topical and transdermal applications. Microemulsion nomenclature and composition, with particular emphasis on choice of surfactant and cosurfactant, is discussed. Methods used to characterize microemulsions are reviewed. Microemulsion formulations for dermal and transdermal delivery of pharmaceutical agents with particular emphasis on anti-inflammatory and anaesthetic agents are critically evaluated. Finally, the issues which warrant further investigation by researchers in order to realize the full potential of the technology are discussed.
Schedule-Dependent Synergistic Effect of Pemetrexed Combined with Gemcitabine against Malignant Pleural Mesothelioma and Non-Small Cell Lung Cancer Cell Lines
Authors: Nagai Shinjiro , Takenaka Kazumasa , Sonobe Makoto , Wada Hiromi , Tanaka Fumihiro
Published: June 2008

Background: Pemetrexed, a multi-targeted antifolate (MTA), is a promising agent in the treatment of malignant pleural mesothelioma (MPM) and non-small cell lung cancer (NSCLC). With the aim of finding an optimal schedule for the combination therapy of MTA and gemcitabine (GEM), we investigated their interaction against an MPM cell line, 211H, and the NSCLC cell lines A549 and H1299. Methods: Combination index analysis was used in 3 different schedules. Cell cycle analysis by flow cytometry and real-time RT-PCR analysis of thymidylate synthase (TS), folylpolyglutamate synthetase (FPGS) and reduced folate carrier 1 (RFC1) genes were performed to understand the biological consequences of their interaction. Results: MTA showed potent cytotoxicity against 211H cells (IC50, 67 nM for 48 h exposure), compared to NSCLC cell lines. Significantly higher expression of FPGS and RFC1 mRNAs in 211H cells were associated with MTA sensitivity. Simultaneous exposure of MTA and GEM was antagonistic in all cell lines tested. Strong synergism was observed in 211H cells when MTA preceded GEM, but the inverted sequence showed antagonism. Similar results were exhibited in H1299 cells, whereas a moderately synergistic effect was observed in A549 cells when GEM preceded MTA. S phase accumulation by MTA treatment partly supported these results. Conclusion: Sequential administration of MTA and GEM is active, and the schedule of MTA followed by GEM is recommended for treating MPM.
Influence of an Antioxidant Vitamin-Enriched Drink on Pre- and Post-Exercise Lymphocyte Antioxidant System
Authors: Sureda Antoni , Tauler Pedro , Aguiló Antoni , Cases Nuria , Llompart Isabel , Tur Josep A. , Pons Antoni
Published: June 2008

Background/Aims: Our aim was to determine whether the consumption of a functional drink enriched with vitamin C and vitamin E could alleviate exercise-induced oxidative damage in lymphocytes. Methods: Fourteen male amateur trained runners (32–36 years old) were randomized to receive antioxidant supplementation (152 mg vitamin C/day and 50 mg vitamin E/day) or placebo for 1 month in a double-blind study, and participated in a half-marathon race. The volunteers did not take any other antioxidant supplements. Blood samples were taken before and after the half-marathon and after 3 h recovery. Results: Exercise increased lymphocyte malondialdehyde levels only in the placebo group (p < 0.001). Lymphocytes from the supplemented group accumulated more vitamin C and vitamin E than placebo after exercise and recovery (p < 0.05). Catalase and glutathione peroxidase activities increased only in the supplemented group after exercise, whereas superoxide dismutase activity increased in both groups (p < 0.05). Heme oxygenase-1 expression was enhanced during the recovery period only in the placebo group (p < 0.01). Bcl-2 expression decreased after exercise only in the placebo group and remained low during the recovery (p < 0.001). Conclusions: Intense exercise increases lipid peroxidation, decreases Bcl-2 expression and induces an antioxidant response in lymphocytes. Supplementation with moderate levels of antioxidant vitamins reduces exercise-induced oxidative damage, but without blocking the cellular adaptation to exercise.
Chondrogenic Potential of Mesenchymal Stem Cells from Patients with Rheumatoid Arthritis and Osteoarthritis: Measurements in a Microculture System
Authors: Dudics Valėria , Kunstár Aliz , Kovács János , Lakatos Tamás , Géher Pál , Gömör Béla , Monostori Ėva , Uher Ferenc
Published: June 2008

Background: Mesenchymal stem cells (MSCs) have the potential to differentiate into distinct mesenchymal tissues; including cartilage and bone, they can be an attractive cell source for cartilage tissue engineering approaches. Our objective here was to compare the in vitro chondrogenic potential of MSCs isolated from patients with rheumatoid arthritis (RA) and osteoarthritis (OA) with cells from normal donors. Methods: Marrow samples were removed during bone surgery and adherent cell cultures were established. The cells were then passed into a newly developed microaggregate culture system in a medium containing transforming growth factor β3, insulin, dexamethasone and/or demineralized bone matrix. In vitro chondrogenic activity was measured as metabolic sulfate incorporation and type II collagen expression in pellet cultures. Results: Culture-expanded MSCs from RA and OA patients did not differ significantly from the normal population with respect to their chondrogenic potential in vitro. Capability of total protein and proteoglycan synthesis as well as collagen II mRNA expression by cell aggregates was similar for all cell preparations in the presence of the appropriate growth and differentiation factors. Chondroprotective drugs such as chondroitin sulfate and glucosamine enhanced, whereas chloroquine inhibited chondrogenesis in normal donor-derived or patient-derived MSC cultures. Galectin-1, a β-galactoside-binding protein with marked anti-inflammatory activity, stimulated the chondrogenic differentiation of mesenchymal cells in low (<2 μg/ml) concentration. Discussion: These findings show that MSCs from RA and OA patients possess similar chondrogenic potential as MSCs isolated from healthy donors, therefore these cells may serve as a potential new prospect in cartilage replacement therapy.
Mechanical Inhibition of Angiogenesis at the Saphenofemoral Junction in the Surgical Treatment of Varicose Veins
Authors: van Rij André M. , Jones Gregory T. , Hill B. Geraldine , Amer Mohammad , Thomson Ian A. , Pettigrew Ross A. , Packer Stephen G.K.
Published: June 2008

Background—

Saphenofemoral junction (SFJ) ligation has been a major component of surgical intervention for varicose veins; however, recurrence occurs in as many as 40%. Neovascularization with reconnection of the venous channels at the transected SFJ has been identified as the major cause of this recurrence. This randomized controlled study sought to evaluate mechanical suppression of neovascularization at the SFJ, with the use of a synthetic patch, to prevent recurrence after ligation surgery.

Methods and Results—

A total of 389 limbs (from 292 patients) were randomized into either control (SFJ ligation surgery) or patch (SFJ ligation with polytetrafluoroethylene patch of the transected SFJ) groups. All patients underwent clinical assessment, duplex imaging, and air plethysmography studies preoperatively and at 1, 6, 12, and 36 months postoperatively. The patch consistently halved the recurrence rate to 3 years postoperatively in all clinical subgroups. In those patched SFJs that still developed recurrence, evidence of neovascularization circumventing the polytetrafluoroethylene patch was observed by both ultrasound and histology.

Conclusions—

This study demonstrates that use of a polytetrafluoroethylene patch is an effective mechanical suppressant of neovasculogenesis at the SFJ and can be safely used as a strategy to improve long-term outcome of varicose vein surgery.
Results of a Double-Blind, Placebo-Controlled Study to Assess the Safety of Intramuscular Injection of Hepatocyte Growth Factor Plasmid to Improve Limb Perfusion in Patients With Critical Limb Ischemia
Authors: Powell Richard J. , Simons Michael , Mendelsohn Farrel O. , Daniel George , Henry Timothy D. , Koga Minako , Morishita Ryuichi , Annex Brian H.
Published: June 2008

Background—

The Study to Assess the Safety of Intramuscular Injection of Hepatocyte Growth Factor Plasmid to Improve Limb Perfusion in Patients With Critical Limb Ischemia (HGF-STAT trial) determined the effect of hepatocyte growth factor (HGF) plasmid on safety and limb tissue perfusion as measured by transcutaneous oxygen tension (TcP
o
2
) in patients with critical limb ischemia (CLI).

Methods and Results—

Randomized patients with rest pain or ischemic ulcers and TcP
o
2
<40 mm Hg and/or toe pressure <50 mm Hg received placebo or HGF-plasmid intramuscular injection as follows: 0.4 mg at days 0, 14, and 28 (low dose); 4.0 mg at days 0 and 28 (middle dose); or 4.0 mg at days 0, 14, and 28 (high dose). Patients were evaluated for safety, changes in TcP
o
2
and ankle and toe pressure, amputation, and wound healing. Ninety-three of 104 treated patients were evaluated for safety (mean age 70 years, 63% male, 53% diabetic, 64% with tissue loss, mean ankle-brachial index 0.41, and mean toe pressure 26 mm Hg). Adverse events occurred in 86% of the patients, most of which were related to CLI or comorbid conditions and were not different between groups. TcP
o
2
(mean±SE) increased at 6 months in the high-dose group (24.0±4.2 mm Hg, 95% CI 15.5 to 32.4 mm Hg) compared with the placebo (9.4±4.2 mm Hg, 95% CI 0.9 to 17.8), low-dose (11.1±3.7 mm Hg, CI 3.7 to 18.7 mm Hg), and middle-dose (7.3±4.8 mm Hg, CI −2.2 to 17.0 mm Hg) groups (ANCOVA
P
=0.0015). There was no difference between groups in secondary end points, including ankle-brachial index, toe-brachial index, pain relief, wound healing, or major amputation.

Conclusions—

Intramuscular injection of HGF plasmid was safe and well tolerated. Larger studies to determine whether HGF plasmid can improve wound healing and limb salvage in patients with CLI are warranted.
Tracking of Blood Pressure From Childhood to Adulthood
Authors: Chen Xiaoli , Wang Youfa
Published: June 2008

Background—

A large number of studies have examined the tracking of blood pressure (BP) from childhood to adulthood, but the reported findings are inconsistent and few systematic analyses have been conducted.

Methods and Results—

We conducted a systematic search of PubMed for studies that examined the tracking of BP from childhood to adulthood published between January 1970 and July 2006. From 301 retrieved papers, 50 cohort studies met our inclusion criteria and provided 617 data points (Pearson/Spearman correlation coefficients) for systolic BP (SBP) and 547 data points for diastolic BP (DBP) for our meta-analysis. Information on sample characteristics and BP measurement protocols was extracted. Fisher z transformation and random-effects meta–regression analysis were conducted. The reported BP tracking correlation coefficients varied from −0.12 to 0.80 for SBP and from −0.16 to 0.70 for DBP, with an average of 0.38 for SBP and 0.28 for DBP. BP tracking varied significantly by baseline age and length of follow-up. The strength of BP tracking increased with baseline age by 0.012 for SBP (
P
<0.001) and 0.009 for DBP (
P
<0.001) and decreased with follow-up length by 0.008 for SBP (
P
<0.001) and 0.005 for DBP (
P
<0.001). BP tracking did not vary markedly across the number of BP measurements or race/population groups.

Conclusions—

Data from diverse populations show that the evidence for BP tracking from childhood into adulthood is strong. Childhood BP is associated with BP in later life, and early intervention is important.
Role of Conduction Velocity Restitution and Short-Term Memory in the Development of Action Potential Duration Alternans in Isolated Rabbit Hearts
Authors: Mironov Sergey , Jalife José , Tolkacheva Elena G.
Published: June 2008

Background—

Spatially discordant alternans (SDA) has been linked to life-threatening arrhythmias. The mechanisms underlying SDA development in cardiac tissue remain unclear.

Methods and Results—

We investigated the role of conduction velocity (CV) restitution and short-term memory in the organization and evolution of alternans in action potential duration using high-resolution optical mapping of the epicardial surface in 8 isolated, Langendorff-perfused rabbit hearts. To assess the spatial organization of alternans, we tracked the evolution of nodal lines that separate out-of-phase regions of SDA. We measured the action potential duration heterogeneity index and maximal slope of CV restitution and estimated the effects of short-term memory by calculating time constant of action potential duration accommodation (τ). We found that 2 mechanisms underlie the development of SDA in the heart, leading to 2 distinct behaviors of nodal lines. The first mechanism is based on steep CV restitution and is associated with small τ and stable nodal lines. The second mechanism is associated with short-term memory (large τ) and is characterized by shallow CV restitution and unstable behavior of nodal lines. The maximum slope of the CV restitution was steeper (18.16±3.34 m/s
2
) and τ was smaller (τ=4.31±0.33 stimuli) for areas with stable nodal lines than for areas with unstable nodal lines (6.32±0.96 m/s
2
and τ=10.3±1.84 stimuli;
P
<0.01).

Conclusions—

Our results provide new insight into the mechanisms underlying SDA formation in the rabbit heart. Specifically, our results suggest that a new mechanism associated with short-term memory underlies SDA formation in the heart, in addition to steep CV restitution.
Effect of Doxazosin Gastrointestinal Therapeutic System as Third-Line Antihypertensive Therapy on Blood Pressure and Lipids in the Anglo-Scandinavian Cardiac Outcomes Trial
Authors: Chapman Neil , Chang Choon Lan , Dahlöf Björn , Sever Peter S. , Wedel Hans , Poulter Neil R.
Published: June 2008

Background—

The role of doxazosin in treatment of hypertension remains controversial.

Methods and Results—

We evaluated the effects on blood pressure (BP) and biochemical parameters of doxazosin GITS (gastrointestinal therapeutic system) as a third-line antihypertensive agent among 10 069 participants in the Anglo-Scandinavian Cardiac Outcomes Trial–Blood Pressure Lowering Arm (ASCOT-BPLA) whose BP remained above 140/90 mm Hg (130/80 mm Hg in those with diabetes mellitus). Among those who received doxazosin, mean age was 63 years (SD 9 years), 79% were male, and 32% had diabetes. Doxazosin was initiated a median of 8 months (interquartile range 3 to 24 months) after randomization and was added to a mean of 2.0 (SD 0.3) other antihypertensive drugs; the mean starting and final doses were 4.1 (SD 0.6) and 7.0 (SD 3.1) mg, respectively. During a median of 12 months (interquartile range 4 to 31 months) of uninterrupted doxazosin treatment, during which other antihypertensive treatments remained unchanged, mean BP fell 11.7/6.9 mm Hg (SD 18.8/9.6 mm Hg,
P
<0.0001) from 158.7/89.2 mm Hg (SD 18.3/10.6 mm Hg). After the addition of doxazosin, 29.7% of participants achieved target BP. There was no apparent excess of heart failure among doxazosin users. There were associated modest favorable effects on plasma lipid profiles, but a small rise in fasting plasma glucose was observed. Doxazosin was generally well tolerated, with 7.5% of participants discontinuing the drug because of adverse events, most frequently dizziness, fatigue, headache, and edema.

Conclusions—

α-Blockers are no longer recommended as add-on therapy in some hypertension guidelines. However, although they are nonrandomized and were not placebo-controlled, the present findings suggest that doxazosin is a safe and effective third-line antihypertensive agent.