bluuebunny/crossref_metadata_2025 huggingface dataset:
Acute disseminated encephalomyelitis
Authors: Garg R K
Published: February 2003

Acute disseminated encephalomyelitis (ADEM) is an acute demyelinating disorder of the central nervous system, and is characterised by multifocal white matter involvement. Diffuse neurological signs along with multifocal lesions in brain and spinal cord characterise the disease. Possibly, a T cell mediated autoimmune response to myelin basic protein, triggered by an infection or vaccination, underlies its pathogenesis. ADEM is a monophasic illness with favourable long term prognosis. The differentiation of ADEM from a first attack of multiple sclerosis has prognostic and therapeutic implications; this distinction is often difficult. Most patients with ADEM improve with methylprednisolone. If that fails immunoglobulins, plasmapheresis, or cytotoxic drugs can be given. Recent literature suggests that a significant proportion of patients with ADEM will later develop multiple sclerosis; however, follow up experience from developing countries does not support this view.
Hereditary haemorrhagic telangiectasia (Osler-Weber-Rendu syndrome): a view from the 21st century
Authors: Begbie M E , Wallace G M F , Shovlin C L
Published: February 2003

Hereditary haemorrhagic telangiectasia (HHT) affects one in 5−8000, and no longer can be viewed as solely causing anaemia (due to nasal and gastrointestinal bleeding) and characteristic mucocutaneous telangiectasia. Arteriovenous malformations commonly occur, and in the pulmonary and cerebral circulations demand knowledge of risks and benefits of asymptomatic screening and treatment. HHT is inherited as an autosomal dominant trait and there is no age cut off when apparently unaffected offspring of an individual with HHT can be told they are unaffected. This review focuses on the evolving evidence base for HHT management, issues regarding pregnancy and prothrombotic treatments, and discusses the molecular and cellular changes that underlie this disease.
Evaluation and treatment of dyspepsia
Authors: Jones M P
Published: February 2003

Dyspepsia is a common symptom. Dyspeptic symptoms may be caused by a variety of conditions such as peptic ulcer disease, gastro-oesophageal reflux, and malignancy. Most often, however, no cause is identified and dyspepsia is deemed to be functional. While symptom severity does influence frequency of consultation, dyspeptic consulters also differ from non-consulters with respect to symptom perception and anxiety. This highlights the importance of understanding the patient’s agenda early in the course of evaluation. Patients over the age of 55 years or with alarm symptoms should be referred for prompt endoscopy. In the absence of other clinically apparent aetiologies, uninvestigated dyspeptics can be either tested and treated for Helicobacter pylori or empirically treated with proton pump inhibitors. Uninvestigated dyspeptics failing empiric therapy should be referred for evaluation that includes endoscopy. Further therapy with prokinetics, tricyclic antidepressants, fundal relaxants, antidepressants, or psychotherapy is guided by predominant symptoms and assessment of possible psychiatric factors.
Evolution of diabetes medical nutrition therapy
Authors: Franz M J , Warshaw H , Daly A E , Green-Pastors J , Arnold M S , Bantle J
Published: February 2003

Research supports the importance of medical nutrition therapy in achieving diabetes treatment goals. For persons requiring insulin therapy, the first priority is to integrate an insulin regimen into the patient’s lifestyle. For type 2 diabetes, the priority is to focus on lifestyle strategies (that is, nutrition and exercise) that will improve metabolic outcomes at diagnosis and as the disease progresses. Patients with diabetes need nutrition recommendations that are supported by scientific evidence and that can be easily understood and translated into everyday life. To achieve positive outcomes, a coordinated team effort that provides continued education and support is essential.
HIV viral suppression in the era of antiretroviral therapy
Authors: Thaker H K , Snow M H
Published: February 2003

Altogether 42 million people worldwide have been infected with HIV, and 12 million have died over the last 20 years. Effective antiretroviral therapy has lead to sustained HIV viral suppression and immunological recovery in patients who have been infected with the virus. The incidence of AIDS has declined in the Western world with the introduction of effective antiretroviral therapy. Questions on When to start treatment?, What to start with?, How to monitor patients?, remain heavily debated. Adherence to antiretroviral treatment remains the cornerstone of effective treatment, and failure to adhere is the strongest predictor of virological failure. Long term therapy can lead to metabolic complications. Resource poor countries are dealing with difficult issues such as mother to child prevention of HIV transmission. Other treatment options are now available, with the recent introduction of fusion inhibitors, second generation non-nucleoside reverse transcriptase inhibitors, and nucleotide reverse transcriptase inhibitors to clinical practice.
Total arterial revascularisation as a primary strategy for coronary artery bypass grafting
Authors: Naik M J , Abu-Omar Y , Alvi A , Wright N , Henderson A , Channon K , Forfar J C , Taggart D P
Published: February 2003

Background

Bilateral internal thoracic arteries confer improved survival benefit after coronary artery bypass grafting (CABG). Despite increasing evidence, the use of arterial conduits has not been accepted as a primary practice in most of the centres in the UK for various reasons. A series of patients has been analysed to assess the feasibility of total arterial revascularisation as a primary strategy in patients requiring first time CABG.

Methods

Altogether 245 patients undergoing first time CABG by one surgeon, from June 1999 to October 2000, were studied. Group 1 consisted of 165 patients undergoing total arterial revascularisation (using bilateral internal thoracic and radial arteries) and group 2 consisted of 80 patients undergoing conventional CABG (using one internal thoracic artery and supplemental veins). Thirty day mortality and early morbidity with particular reference to resternotomy for bleeding, cerebrovascular accidents, renal failure, and sternal dehiscence were the main outcome measures.

Results

Patients in group 1 were younger (mean (SD) 60 (10) v 65 (9) years; p<0.001), had lower Parsonnet scores (mean (SD) 5 (5) v 11 (7); p<0.001), and better left ventricular function. Both groups received a similar number of grafts. The percentage of patients undergoing total arterial revascularisation rose from 44% in the first three months to over 75% in the three latter three month periods. Overall 30 day mortality was 1.3%, one patient (0.6%) in group 1 and two patients (2.5%) in group 2. There was a similar incidence of postoperative complications and length of median postoperative stay in both groups.

Conclusion

Total arterial revascularisation can be adopted as a primary strategy in most patients undergoing CABG with no increase in mortality or morbidity.
Pupillary evaluation for differential diagnosis of coma
Authors: Tokuda Y , Nakazato N , Stein G H
Published: February 2003

Objectives

To determine the usefulness of bedside evaluation of pupils in determining the aetiology of coma by adopting a probabilistic approach.

Patients and methods

One hundred and fifteen consecutive patients presenting with coma were enrolled in this prospective cohort during the 12 month study period in the emergency room of a community teaching hospital. Patients underwent structured clinical examinations and laboratory and imaging tests. Assignment of aetiology of coma was based on strict adherence to predetermined criteria and achieved by consensus of the two physician investigators. One year follow up was obtained in all patients.

Results

Aetiology of coma was determined in 98% of the patients. It was metabolic in 69 patients (60%) and structural in 46 patients (40%). Metabolic causes included drug overdose, acute alcohol intoxication, hypoglycaemia, sepsis, and pneumonia. Structural causes included intracerebral haemorrhage, subarachnoid haemorrhage, cerebral infarction, subdural haematoma, and epidural haematoma. Multivariate logistic regression analysis showed light reflex loss (likelihood ratio for positive test result 3.59) and anisocoria (likelihood ratio for positive test result 9.0) as independent predictors of structural origin.

Conclusions

In this prospective study of patients presenting to the emergency room of a community based teaching hospital with coma, in about 60% the coma is of metabolic origins and in about 40% of structural origins. Light reflex loss and anisocoria suggest a structural aetiology.
Drotrecogin alfa (activated): a novel therapeutic strategy for severe sepsis
Authors: Pastores S M
Published: February 2003

Recent studies have highlighted the close link between activation of the coagulation system and the inflammatory response in the pathophysiology of severe sepsis. The protein C anticoagulant pathway plays an integral part in modulating the coagulation and inflammatory responses to infection. In patients with sepsis, endogenous protein C levels are decreased, shifting the balance toward greater systemic inflammation, coagulation, and cell death. On the basis of a single large randomised phase 3 trial, drotrecogin alfa (activated), a recombinant form of human activated protein C, was recently approved for the treatment of adult patients with severe sepsis and a high risk of death. Since its approval, several questions have been raised regarding the appropriate use of this agent. Given the increased risk of serious bleeding and the high cost of treatment, drotrecogin alfa (activated) should be reserved at this time for the most acutely ill patients with severe sepsis who meet the criteria that were used in the phase 3 trial.
Are medical reports on fitness to drive trustworthy?
Authors: Steier T S , Kitai E , Wiener A , Kahan E
Published: February 2003

Purpose

Previous studies have shown that physicians often have poor knowledge of the medical restriction on fitness to drive, or submit poor quality medical reports. To determine the reliability of physicians’ reports on fitness to drive, the medical data provided on the standard medical fitness form was compared with the additional data collected on repeated assessment.

Methods

A random sample of 100 applicants for a driver’s licence aged more than 49 years who submitted the standard medical form were asked to provide, from their regular family doctor, confirmation of their health status and/or additional medical data in order to make a re-evaluation.

Results

The rate of rejection for a licence for medical reasons was 3% on the basis of the standard evaluation and 17% on the basis of the re-evaluation (p<0.001).

Conclusion

This study shows that the random evaluation of physician assessments of applicants for a driver’s licence increases the detection rate of medical problems that can affect fitness to drive. The alarming difference in the rate of rejection between the two assessments may reflect a lackadaisical attitude of medical professionals toward the licence assessment procedure and/or physician unawareness of the medical restrictions on fitness to drive. Results of this study suggest that this subject must be included in medical education programmes.
Unusual complications of thyroid carcinoma
Authors: Owen P J D , Lazarus J H , Morse R E
Published: February 2003

Thyroid carcinomas are the most frequent endocrine malignancies. Complications may arise from an established malignancy and these may lead to the initial clinical presentation or cause subsequent problems. In this case report two elderly patients with differentiated and undifferentiated thyroid carcinomas who suffered unusual medical complications are described. The incidence and treatment of thyroid carcinoma is discussed and the importance of fine needle aspiration of thyroid nodules and the recognition of iodine containing radiographic contrast media in the causation of iodine induced thyrotoxicosis is highlighted.
Late small bowel obstruction after blunt abdominal trauma
Authors: Maharaj D , Perry A , Ramdass M , Naraynsingh V
Published: February 2003

Blunt abdominal trauma with intraperitoneal injury usually presents acutely. On rare occasions, such patients can present later on with features of small bowel obstruction due to stricture formation. It is thought that such a delayed stricture is due to subclinical bowel perforation, localised gut ischaemia, or injury to the mesenteric vasculature. This case demonstrates the mesenteric vascular injury theory to be the cause of the bowel stricture.
Phantom lymphadenopathy. An association with chronic fatigue syndrome
Authors: Shee C D
Published: February 2003

Ten patients with self diagnosed enlarged lymph glands were referred to a general medicine outpatient clinic and careful examination did not confirm lymphadenopathy. All patients also complained of severe chronic fatigue associated with aches and miscellaneous somatic symptoms, and fulfilled criteria for diagnosis of chronic fatigue syndrome (CFS). Phantom lymphadenopathy may be a symptom in some people with CFS, and possible reasons for this are discussed.
Researching the green fuse: an historical memoir
Authors: King John
Published: February 2003

The author outlines the major milestones in his 40-year career in plant research. His research program might be described, broadly, as explorations into the physiology and biochemistry of plants and their cells using physiological, biochemical, genetic, molecular biological and chemical techniques and technologies. The main areas encompassed by the program are the pathways of biosynthesis of branched-chain amino acids, pantothenate, folates and one-carbon units, uptake of organic and inorganic sources of nitrogen by plant cells, and somatic hybridization and genetic transformation of plant protoplasts. Many of these investigations were carried out with the aid of auxotrophic and resistance genetic variants selected either from cultures of Datura innoxia cells or from among mutagenized populations of Arabidopsis thaliana seedlings. Some technologies found to be especially useful were plant cell and tissue culture, detection of 14C-labelled isotopes in metabolic intermediates, isolation, purification and characterization of enzymes, and most recently, 13C nuclear magnetic resonance (NMR) spectroscopy.Key words: Arabidopsis, Datura, biochemical genetic variants, tissue culture, nitrogen metabolism.
Ecological relationships of wild rice, Zizania spp. 10. Effects of sediment and among-population variations on plant density in Zizania palustris
Authors: Lee P F
Published: February 2003

The influence of nutrients and intraspecific variations in growth form were examined for their effect on plant density in stands of northern wild rice, Zizania palustris L. In a field situation, densities of a size-restricted wild rice population increased as nutrient levels in the sediment increased. No self-thinning occurred until the population density exceeded 350 plants/m2. A series of controlled experiments examined whether these wild rice densities were determined by resource depletion and (or) intraspecific competition. As nutrient levels increased under constant plant densities, tillering, dry weight, and seed production increased more for populations with the capacity for higher vegetative and reproductive potential. As plant densities increased under constant nutrient levels, height, weight, and seed production declined but inequality of individual plants increased. When both nutrient levels and population densities were increased simultaneously, seed production per panicle declined at higher densities under unfertilized conditions but was unaffected in the treatment with the highest fertilizer level. It was hypothesized that plant densities under field conditions were the result of an integrated mechanism that was influenced by nutrients and the degree of asymmetric competition characteristic of the population. As nutrient levels increase, plant densities would be expected to decrease for populations with high levels of asymmetric competition and increase for populations with low levels of asymmetric competition.Key words: wild rice, density effects, nutrients, intraspecific variation.
Polyphyly of the spring-parsleys (Cymopterus): molecular and morphological evidence suggests complex relationships among the perennial endemic genera of western North American Apiaceae
Authors: Downie Stephen R , Hartman Ronald L , Sun Feng-Jie , Katz-Downie Deborah S
Published: February 2003

Cladistic analyses of DNA sequences from the nuclear rDNA internal transcribed spacer region and cpDNA rps16 intron and, for a subset of taxa, the cpDNA trnF-trnL-trnT locus were carried out to evaluate the monophyly of Cymopterus and to ascertain its phylogenetic placement among the other perennial genera of Apiaceae (Umbelliferae) subfamily Apioideae endemic to western North America. To elucidate patterns in the evolution of specific fruit characters and to evaluate their utility in circumscribing genera unambiguously, additional evidence was procured from cross-sections of mature fruits and the results of cladistic analysis of 25 morphological characters. Analyses of the partitioned data sets resulted in weakly supported and largely unresolved phylogenetic hypotheses, possibly due to the rapid radiation of the group, whereas the combined analysis of all molecular evidence resulted in a well-resolved phylogeny with higher bootstrap support. The traditionally used fruit characters of wing shape and composition and orientation of mericarp compression are highly variable. The results of these analyses reveal that Cymopterus and Lomatium, the two largest genera of western North American Apiaceae, are polyphyletic, and that their species are inextricably linked with those of other endemic perennial genera of the region (such as, Aletes, Musineon, Oreoxis, Pseudocymopterus, Pteryxia, and Tauschia), many of which are also not monophyletic. Prior emphasis on characters of the fruit in all systems of classification of the group has led to highly artificial assemblages of species. A complete reassessment of generic limits of all western endemic Apiaceae is required, as is further systematic study of this intractable group.Key words: Apiaceae, Cymopterus, phylogeny, ITS, rps16 intron, morphology.
Formation of the charge-transfer exciton in 1,3,5-triphenyl-2-pyrazoline nanocrystals
Authors: Fu Hongbing , Xiao Debao , Xie Ruimin , Ji Xuehai , Yao Jian-Nian
Published: February 2003

A series of 1,3,5-triphenyl-2-pyrazoline (TPP) nanocrystals were prepared by the reprecipitation method. The electronic transitions of TPP nanocrystals have been studied using both absorption and fluorescence spectra. An absorption feature at about 400 nm gradually appeared with increasing nanocrystal size. This feature resulted from the formation of the charge-transfer (CT) exciton in nanocrystals. It was also supported by the longer decay time of the nanocrystal emission from CT compared with that of the solution emission from S1 at 298 K. On the other hand, the different behavior of the molecular ππ* and nπ* transitions originates from the different overlapping modes of the pyrazoline π orbital and n-electron orbital, according to the molecular model calculations. The nanocrystal emission from both the S1 and CT states was found at 77 K; moreover, the emission intensity redistributed from S1 to CT with increasing nanocrystal size. In contrast, at 298 K, only the emission from the CT states was observed, since the thermal fluctuation easily relaxes the excited electrons into CT states through vibration. Key words: reprecipitation method, organic nanocrystals, charge-transfer exciton, size-dependent property.
COMPUTING THE DIAMETER OF A POINT SET
Authors: MALANDAIN GRÉGOIRE , BOISSONNAT JEAN-DANIEL
Published: February 2003

Given a finite set of points [Formula: see text] in ℝd, the diameter of [Formula: see text] is defined as the maximum distance between two points of [Formula: see text]. We propose a very simple algorithm to compute the diameter of a finite set of points. Although the algorithm is not worst-case optimal, an extensive experimental study has shown that it is extremely fast for a large variety of point distributions. In addition, we propose a comparison with the recent approach of Har-Peled5 and derive hybrid algorithms to combine advantages of both approaches.
LABELING POINTS WITH RECTANGLES OF VARIOUS SHAPES
Authors: KOIKE ATSUSHI , NAKANO SHIN-ICHI , NISHIZEKI TAKAO , TOKUYAMA TAKESHI , WATANABE SHUHEI
Published: February 2003

We deal with a map-abeling problem, named LOFL (Left-part Ordered Flexible Labeling), to label a set of points in a plane in the presence of polygonal obstacles. The label for each point is selected from a set of rectangles with various shapes satisfying the left-part ordered property, and is placed near to the point after scaled by a scaling factor σ which is common to all points. In this paper, we give an optimal O((n + m) log (n + m)) algorithm to decide the feasibility of LOFL for a fixed scaling factor σ, and an O((n + m) log 2 (n + m)) time algorithm to find the largest feasible scaling factor σ, where n is the number of points and m is the total number of edges of the polygonal obstacles.
ON A THEOREM OF GOUSSAROV
Authors: CONANT J.
Published: February 2003

In this paper, the easier methods of my thesis are applied to give a simple proof of a theorem of Goussarov. This theorem relates two possible notions of finite type equivalence of knots, links, or string links, showing that the resulting filtrations are the same up to a degree shift by a factor of two. This is then applied to the situation of rooted claspers to show that rooted clasper surgeries of sufficiently high degree must preserve type k invariants. As a consequence, grope cobordisms of sufficiently high class must preserve type k invariants. This result is applied in [CT] to show Theorem 2 of that paper.
THE g-OPERATIONAL CALCULUS
Authors: PAP ENDRE , TAKAČI DJURDJICA , TAKAČI ARPAD
Published: February 2003

Using the g-calculus, introduced earlier by E. Pap, the g-operator field ℱgis introduced analogously to the classical field of Mikusiňski operators ℱ. The obtained results enable the solving of a certain nonlinear PDE of the Burgers type in a wider framework of the generalized functions, which is a generalization of the earlier obtained result.
A Double Life: Academic Physician and Androgen Physiologist
Authors: Wilson Jean D.
Published: January 2003

▪ Abstract  My work in physiology was designed to investigate the process of androgen action within target cells and to use this information to provide insight into the clinical disorders of androgen action. The discovery that the circulating male androgen testosterone is 5α-reduced to a more potent hormone, dihydrotestosterone, in target tissues and that dihydrotestosterone and testosterone work by binding to the same androgen receptor protein has provided insight into the inherited syndromes of androgen resistance that impair the formation of the male urogenital tract during embryogenesis and into the role of continued dihydrotestosterone formation in the pathogenesis of prostatic hyperplasia in dogs and men.
Regulation of Na/Pi Transporter in the Proximal Tubule
Authors: Murer Heini , Hernando Nati , Forster Ian , Biber Jürg
Published: January 2003

▪ Abstract  The physiological tuning and pathophysiological alterations of renal proximal reabsorption of inorganic phosphate can be ascribed to the net amount of the Na/Pi-cotransporter NaPi-IIa localized in the brush border membrane. The net amount of NaPi-IIa appears to be the result of an endocytotic rate regulated by a complex network of different protein kinases. New approaches demonstrated that NaPi-IIa is part of heteromeric protein complexes, organized by PDZ (postsynaptic protein PSD95, Drosophila junction protein Disc-large, tight junction protein ZO-1) proteins. Such complexes are thought to play important roles in the apical positioning and regulated endocytosis of NaPi-IIa and therefore such interactions have to be considered when explaining proximal phosphate ion reabsorption.
Macula Densa Cell Signaling
Authors: Bell P. Darwin , Lapointe Jean Yves , Peti-Peterdi János
Published: January 2003

▪ Abstract  Macula densa cells are renal sensor elements that detect changes in distal tubular fluid composition and transmit signals to the glomerular vascular elements. This tubuloglomerular feedback mechanism plays an important role in regulating glomerular filtration rate and blood flow. Macula densa cells detect changes in luminal sodium chloride concentration through a complex series of ion transport-related intracellular events. NaCl entry via a Na:K:2Cl cotransporter and Cl exit through a basolateral channel lead to cell depolarization and increases in cytosolic calcium. Na/H exchange (NHE2) results in cell alkalization, whereas intracellular [Na] is regulated by an apically located H(Na)-K ATPase and not by the traditional basolateral Na:K ATPase. Communication from macula densa cells to the glomerular vascular elements involves ATP release across the macula densa basolateral membrane through a maxi-anion channel. The adaptation of multi-photon microscopy is providing new insights into macula densa-glomerular signaling.
Paracrine Factors in Tubuloglomerular Feedback: Adenosine, ATP, and Nitric Oxide
Authors: Schnermann Jürgen , Levine David Z.
Published: January 2003

▪ Abstract  The tubuloglomerular feedback response, the change in afferent arteriolar tone caused by a change in NaCl concentration at the macula densa, is likely initiated by the generation of a vasoactive mediator within the confines of the juxtaglomerular apparatus. Substantial progress has been made in identifying the nature of this mediator and the factors that modulate its effect on vascular tone. In support of earlier studies using P1 purinergic antagonists, the application of the knockout technique has shown that adenosine 1 receptors are absolutely required for eliciting TGF responses. The background level of angiotensin II appears to be an important cofactor determining the efficiency of A1AR-induced vasoconstriction, probably through a synergistic interaction at the level of the G protein–dependent transduction mechanism. The source of the adenosine is still unclear, but it is conceivable that adenosine is generated extracellularly from released ATP through a cascade of ecto-nucleotidases. There is also evidence that ATP may activate P2 receptors in preglomerular vessels, which may contribute to autoregulation of renal vascular resistance. Nitric oxide (NO), generated by the neuronal isoform of nitric oxide synthase in macula densa cells, reduces the constrictor effect of adenosine, but the regulation of NO release and its exact role in states of TGF-induced hyperfiltration are still unclear.
Cell Biology of Acid Secretion by the Parietal Cell
Authors: Yao Xuebiao , Forte John G.
Published: January 2003

▪ Abstract  Acid secretion by the gastric parietal cell is regulated by paracrine, endocrine, and neural pathways. The physiological stimuli include histamine, acetylcholine, and gastrin via their receptors located on the basolateral plasma membranes. Stimulation of acid secretion typically involves an initial elevation of intracellular calcium and/or cAMP followed by activation of a cAMP-dependent protein kinase cascade that triggers the translocation and insertion of the proton pump enzyme, H,K-ATPase, into the apical plasma membrane of parietal cells. Whereas the H,K-ATPase contains a plasma membrane targeting motif, the stimulation-mediated relocation of the H,K-ATPase from the cytoplasmic membrane compartment to the apical plasma membrane is mediated by a SNARE protein complex and its regulatory proteins. This review summarizes the progress made toward an understanding of the cell biology of gastric acid secretion. In particular we have reviewed the early signaling events following histaminergic and cholinergic activation, the identification of multiple factors participating in the trafficking and recycling of the proton pump, and the role of the cytoskeleton in supporting the apical pole remodeling, which appears to be necessary for active acid secretion by the parietal cell. Emphasis is placed on identifying protein factors that serve as effectors for the mechanistic changes associated with cellular activation and the secretory response.
In vivo NMR Studies of the Glutamate Neurotransmitter Flux and Neuroenergetics: Implications for Brain Function
Authors: Rothman Douglas L. , Behar Kevin L. , Hyder Fahmeed , Shulman Robert G.
Published: January 2003

▪ Abstract  Until very recently, non-invasive measurement of the glutamate-glutamine cycle in the intact mammalian brain had not been possible. In this review, we describe some studies that have led to quantitative assessment of the glutamate-glutamine cycle (Vcyc), as well as other important metabolic fluxes (e.g., glucose oxidation, CMRglc(ox)), with13C magnetic resonance spectroscopy (MRS) in vivo. These13C MRS studies clearly demonstrate that glutamate released from presynaptic neurons is taken up by the astrocyte for subsequent glutamine synthesis. Contrary to the earlier concept of a small, metabolically inactive neurotransmitter pool, in vivo13C MRS studies demonstrate that glutamate release and recycling is a major metabolic pathway that cannot be distinguished from its actions of neurotransmission. Furthermore, the in vivo13C MRS studies demonstrate in the rat cerebral cortex that increases in Vcycand neuronal CMRglc(ox)are linearly related with a close to 1:1 slope. Measurements in human cerebral cortex are in agreement with this result. This relationship is consistent with more than two thirds of the energy yielded by glucose oxidation being used to support events associated with glutamate neurotransmission, and it supports a molecular model of a stoichiometric coupling between glutamate neurotransmission and functional glucose oxidation.13C MRS measurements of resting human cerebral cortex have found a high level of glutamate-glutamine cycling. This high resting neuronal activity, which is subtracted away in brain mapping studies by positron emission tomography (PET) and functional magnetic resonance imaging (fMRI), has significant implications for the interpretations of functional imaging data. Here we review and discuss the importance of neurotransmission and neuroenergetics as measured by13C MRS for understanding brain function and interpreting fMRI.
The Gastric Biology ofHelicobacter pylori
Authors: Sachs George , Weeks David L. , Melchers Klaus , Scott David R.
Published: January 2003

▪ Abstract  Helicobacter pylori is a neutralophilic, gram-negative, ureolytic organism that is able to colonize the human stomach but does not survive in a defined medium with a pH <4.0 unless urea is present. In order to live in the gastric environment, it has developed a repertoire of acid resistance mechanisms that can be classified into time-independent, acute, and chronic responses. Time-independent acid resistance depends on the structure of the organism's inner and outer membrane proteins that have a high isoelectric point, thereby reducing their proton permeability. Acute acid resistance depends on the constitutive synthesis of a neutral pH optimum urease that is an oligomeric Ni2+-containing heterodimer of UreA and UreB subunits. Gastric juice urea is able to rapidly access intrabacterial urease when the periplasmic pH falls below ∼6.2 owing to pH-gating of a urea channel, UreI. This results in the formation of NH3, which then neutralizes the bacterial periplasm to provide a pH of ∼6.2 and an inner membrane potential of −101 mV, giving a proton motive force of ∼−200 mV. UreI is a six-transmembrane segment protein, with homology to the amiS genes of the amidase gene cluster and to UreI of Helicobacter hepaticus and Streptococcus salivarius. Expression of these UreI proteins in Xenopus oocytes has shown that UreI of H. pylori and H. hepaticus can transport urea only at acidic pH, whereas that of S. salivarius is open at both neutral and acidic pH. Site-directed mutagenesis and chimeric analysis have identified amino acids implicated in maintaining the closed state of the channel at neutral pH and other amino acids that play a structural role in channel function. Deletion of ureI abolishes the ability of the organism to survive in acid and also to colonize the mouse or gerbil stomach. However, if acid secretion is inhibited in gerbils, the deletion mutants do colonize but are eradicated when acid secretion is allowed to return, showing that UreI is essential for gastric survival and that the habitat of H. pylori at the gastric surface must fall to pH 3.5 or below. The chronic response is from increased Ni2+insertion into the apo-enzyme, which results in a threefold increase in urease, which is also dependent on expression of UreI. This allows the organism to live in either gastric fundus or gastric antrum depending on the level of acidity at the gastric surface. There are other effects of acid on transcript stability that may alter levels of protein synthesis in acid. Incubation of the organism at acidic pH also results in regulation of expression of a variety of genes, such as some outer membrane proteins, that constitutes an acid tolerance response. Understanding of these acid resistance and tolerance responses should provide novel eradication therapies for this carcinogenic gastric pathogen.
Physiology of Gastric Enterochromaffin-Like Cells
Authors: Prinz Christian , Zanner Robert , Gratzl Manfred
Published: January 2003

▪ Abstract  Enterochromaffin-like (ECL) cells are neuroendocrine cells in the gastric mucosa that control acid secretion by releasing histamine as a paracrine stimulant. The antral hormone gastrin and the neural messenger pituitary adenylyl cyclase–activating peptide (PACAP) potently stimulate histamine synthesis, storage, and secretion by ECL cells. Histamine is stored in secretory vesicles via V-type ATPases and vesicular monoamine transporters of subtype 2 (VMAT-2). Plasmalemmal calcium entry occurs via L-type calcium channels upon stimulation with secretagogues. K+ and Cl− channels maintain the membrane potential. Calcium-triggered exocytosis of histamine is mediated by interacting SNARE proteins, especially by synaptobrevin and SNAP-25. Dynamins and amphiphysins appear to play a key role in endocytosis. ECL cells are under transcriptional control of various hormones. Gastrin stimulates transcriptional activity of the histidine decarboxylase (HDC), VMAT-2, and chromogranin A promoter by activation of Sp1 elements and CREB. During chronic Helicobacter pylori infection, pro-inflammatory cytokines are released that can also affect ECL cells, thus impairing their secretory function and viability, which can predispose to hypochlorhydria and gastric carcinogenesis.
Insights into the Regulation of Gastric Acid Secretion Through Analysis of Genetically Engineered Mice
Authors: Samuelson Linda C. , Hinkle Karen L.
Published: January 2003

▪ Abstract  The regulation of acid secretion in the stomach involves a complex network of factors that stimulate secretion in response to the ingestion of a meal and maintain homeostasis of gastric pH. Genetically engineered mouse models have provided a new opportunity to investigate the importance and function of specific molecules and pathways involved in the regulation of acid secretion. Mouse mutants with disruptions in the three major stimulatory pathways for acid secretion in parietal cells, gastrin, histamine, and acetylcholine, have been generated. Disruption of the gastrin pathway results in a major impairment in both basal and induced acid secretion. Histamine and acetylcholine pathway mutants also have significant alterations in acid secretion, although the impairment does not appear to be as severe as in gastrin pathway mutants, perhaps due in part to the hypergastrinemia that occurs. Mice with a disruption in the somatostatin pathway have increased gastric acid secretion, which confirms an important negative regulatory role for this factor. This review discusses these genetically engineered mouse models, as well as others, that provide insight into the complex regulation of in vivo gastric acid secretion. The regulation of growth and cellular morphology of the stomach in these mouse models is also presented. In addition, transgene promoters that are expressed in the gastric epithelium are discussed because these promoters will be important tools to alter cellular physiology in new mouse models in the future.
Lipid Receptors in Cardiovascular Development
Authors: Osborne Nick , Stainier Didier Y. R.
Published: January 2003

▪ Abstract  To most people, concerns over the link between lipids and cardiovascular health most likely end with monitoring their daily consumption of dietary fats. However, it has become increasingly clear that, in addition to effects on adult cardiovascular physiology, lipids also play key roles in the formation of a functioning cardiovascular system. The lysophospholipids, lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P), have come to the forefront as developmental and physiological regulators of the cardiovascular system. In this review, we discuss the function of the G protein–coupled receptors responsible for transducing LPA and S1P signals during development of the vertebrate cardiovascular system, focusing first on their role in angiogenesis and then on their function during embryonic development.
Cardiac Hypertrophy: The Good, the Bad, and the Ugly
Authors: Frey N. , Olson E.N.
Published: January 2003

▪ Abstract  Cardiac hypertrophy is the heart's response to a variety of extrinsic and intrinsic stimuli that impose increased biomechanical stress. While hypertrophy can eventually normalize wall tension, it is associated with an unfavorable outcome and threatens affected patients with sudden death or progression to overt heart failure. Accumulating evidence from studies in human patients and animal models suggests that in most instances hypertrophy is not a compensatory response to the change in mechanical load, but rather is a maladaptive process. Accordingly, modulation of myocardial growth without adversely affecting contractile function is increasingly recognized as a potentially auspicious approach in the prevention and treatment of heart failure. In this review, we summarize recent insights into hypertrophic signaling and consider several novel antihypertrophic strategies.

The same thing that makes you live can kill you in the end.

     —Neil Young
Stress-Activated Cytokines and The Heart: From Adaptation to Maladaptation
Authors: Mann Douglas L.
Published: January 2003

▪ Abstract  The ability of the myocardium to successfully compensate for and adapt to environmental stress ultimately determines whether the heart will decompensate and fail or maintain preserved function. Despite the importance of the myocardial response to environmental stress, very little is known with respect to the biochemical mechanisms that are responsible for mediating and integrating the stress response in the heart. In the present review we summarize recent experimental material suggesting that the cytokines expressed within the myocardium in response to environmental injury, namely tumor necrosis factor (TNF), interleukin-1 (IL-1), and the interleukin-6 (IL-6) family, play an important role in initiating and integrating homeostatic responses. However, these stress-activated cytokines all have the potential to produce cardiac decompensation when expressed at sufficiently high concentrations. Accordingly, the theme to emerge from this review is that the short-term expression of stress-activated cytokines within the heart may be an adaptive response to stress, whereas long-term expression of these molecules may be frankly maladaptive by producing cardiac decompensation.
Permeation and Selectivity in Calcium Channels
Authors: Sather William A. , McCleskey Edwin W.
Published: January 2003

▪ Abstract  Recent advances—both experimental and theoretical—provide a tentative image of the structures in Ca channels that make them exceptionally selective. The image is very different from K channels, which obtain high selectivity with a rigid pore that tightly fits K+ions and is lined by carbonyl oxygens of the polypeptide backbone. Ca channels rely on four glutamate residues (the EEEE locus), whose carboxyl side chains likely reach into the pore lumen to interact with passing Ca2+ions. The structure is thought to be flexible, tightly binding a single Ca2+ion in order to block Na+flux but rearranging to interact with multiple Ca2+ions to allow Ca2+flux. The four glutamates are not equivalent, a fact that seems important for Ca2+permeation. This review describes the experimental evidence that leads to these conclusions and the attempts by theorists to explain the combination of high selectivity and high flux that characterizes Ca channels.
Current Status of Gene Therapy for Inherited Lung Diseases
Authors: Driskell Ryan A. , Engelhardt John F.
Published: January 2003

▪ Abstract  Gene therapy as a treatment modality for pulmonary disorders has attracted significant interest over the past decade. Since the initiation of the first clinical trials for cystic fibrosis lung disease using recombinant adenovirus in the early 1990s, the field has encountered numerous obstacles including vector inflammation, inefficient delivery, and vector production. Despite these obstacles, enthusiasm for lung gene therapy remains high. In part, this enthusiasm is fueled through the diligence of numerous researchers whose studies continue to reveal great potential of new gene transfer vectors that demonstrate increased tropism for airway epithelia. Several newly identified serotypes of adeno-associated virus have demonstrated substantial promise in animal models and will likely surface soon in clinical trials. Furthermore, an increased understanding of vector biology has also led to the development of new technologies to enhance the efficiency and selectivity of gene delivery to the lung. Although the promise of gene therapy to the lung has yet to be realized, the recent concentrated efforts in the field that focus on the basic virology of vector development will undoubtedly reap great rewards over the next decade in treating lung diseases.
The Role of Exogenous Surfactant in the Treatment of Acute Lung Injury
Authors: Lewis James F. , Veldhuizen Ruud
Published: January 2003

▪ Abstract  A number of conditions, such as pneumonia, trauma, or systemic sepsis arising from the gut, may result in the acute respiratory distress syndrome (ARDS). Because of its significant morbidity and mortality, ARDS has been the focus of extensive research. One specific area of interest has been the investigation of the role of the surfactant system in the pathophysiology of this disease. Several studies have demonstrated that alterations of surfactant contribute to the lung dysfunction associated with ARDS, which has led to investigations into the use of exogenous surfactant as a therapy for this syndrome. Clinical experience with surfactant therapy has been variable owing to a number of factors including the nature of the injury at the time of treatment, the specific surfactant preparation utilized, the dose and delivery method chosen, the timing of surfactant administration over the course of the disease, and the mode of ventilation used during and after surfactant administration.
Second Messenger Pathways in Pulmonary Host Defense
Authors: Monick Martha M. , Hunninghake Gary W.
Published: January 2003

▪ Abstract  The alveolar macrophage responds to bacterial infection with the production of inflammatory mediators that include TNFα. Early production of TNFα results in increased bacterial clearance, whereas too much TNFα results in many of the hallmarks of bacterial sepsis. TNFα production is regulated at many levels, including multiple signaling pathways, that lead to transcription, translation, and release of functional TNFα. Interactions of mitogen-activated protein (MAP) kinases, lipid signaling pathways, and oxidant-mediated mechanisms regulate the response of alveolar macrophages to infection. Animal models of sepsis support the central role played by macrophage-derived TNFα in sepsis.
Alveolar Type I Cells: Molecular Phenotype and Development
Authors: Williams Mary C.
Published: January 2003

▪ Abstract  Understanding of the functions and regulation of the phenotype of the alveolar type I epithelial cell has lagged behind studies of its neighbor the type II cell because of lack of cell-specific molecular markers. The recent identification of several proteins expressed by type I cells indicates that these cells may play important roles in regulation of cell proliferation, ion transport and water flow, metabolism of peptides, modulation of macrophage functions, and signaling events in the peripheral lung. Cell systems and reagents are available to characterize type I cell biology in detail, an important goal given that the cells provide the extensive surface that facilitates gas exchange in the intact animal.
Aminophospholipid Asymmetry: A Matter of Life and Death
Authors: Balasubramanian Krishnakumar , Schroit Alan J.
Published: January 2003

▪ Abstract  Maintenance of membrane lipid asymmetry is a dynamic process that influences many events over the lifespan of the cell. With few exceptions, most cells restrict the bulk of the aminophospholipids to the inner membrane leaflet by means of specific transporters. Working in concert with each other, these proteins correct for sporadic incursions of the aminophospholipids to the outer membrane leaflet as a result of bilayer imbalances created by various cellular events. A shift in the relative contribution in each of these activities can result in sustained exposure of the aminophospholipids at the cell surface, which allows capture of the cells by phagocytes before the integrity of the plasma membrane is compromised. The absence of an efficient recognition and elimination mechanism can result in uncontrolled and persistent presentation of self-antigens to the immune system, with development of autoimmune syndromes. To prevent this, phagocytes have developed a diverse array of distinct and redundant receptor systems that drive the postphagocytic events along pathways that facilitate cross-talk between the homeostatic and the immune systems. In this work, we review the basis for the proposed mechanism(s) by which apoptotic ligands appear on the target cell surface and the phagocyte receptors that recognize these moieties.
Regulation of TRP Channels via Lipid Second Messengers
Authors: Hardie Roger C.
Published: January 2003

▪ Abstract  In Drosophila photoreceptors, the light-sensitive current is mediated downstream of phospholipase C by TRP (transient receptor potential) channels. Recent evidence suggests that Drosophila TRP channels are activated by diacylglycerol (DAG) or its metabolites (polyunsaturated fatty acids), possibly in combination with the reduction in phosphatidyl inositol 4,5 bisphosphate (PIP2). Consistent with this view, diacylglycerol kinase is identified as a key enzyme required for response termination. Signaling is critically dependent upon efficient PIP2 synthesis; mutants of this pathway in combination with genetically targeted PIP2 reporters provide unique insights into the kinetics and regulation of PIP2 turnover. Recent evidence indicates that a growing number of mammalian TRP homologues are also regulated by lipid messengers, including DAG, arachidonic acid, and PIP2.